Critical Reviews in Oncology/Hematology 87 (2013) 12–27
Hepatitis B in immunosuppressed cancer patients: Pathogenesis,incidence and prophylaxis
Mario Mandalà a,∗, Stefano Fagiuoli b, Daniela Francisci c, Raffaele Bruno d, Barbara Merelli a,Luisa Pasulo b, Carlo Tondini a, Roberto Labianca a, Fausto Roila e
a Unit of Medical Oncology, Papa Giovanni XXIII Hospital, Bergamo, Italyb Division of Gatroenterology and Hepatology, Papa Giovanni XXIII Hospital, Bergamo, Italy
c Infectious Disease Clinic, S. Maria della Misericordia Hospital, Perugia, Italyd Division of Infectious and Tropical Diseases, IRCCS San Matteo Hospital, University of Pavia, Pavia, Italy
e Medical Oncology, Santa Maria Hospital, Terni, Italy
ackground: Hepatitis B virus (HBV) reactivation in immunosuppressed cancer patients is a serious clinical problem for HBV carriersndergoing chemotherapy, because it may result in severe liver injury and prevent completion of life-saving treatment of the underlyingalignant disease.esign: We reviewed the literature on the incidence, pathogenesis and management of hepatitis B in immunosuppressed cancer patients. The
ole of primary prophylaxis has also been reviewed.
esults: Patients with a previous HBV infection (negative for hepatitis B surface antigen [HBsAg], and positive for both hepatitis B corentibody [anti-HBc] and/or hepatitis B surface antibody [HBsAb]) can experience HBV reactivation. All guidelines support screening ofatients with cancer who are about to undergo potentially immunosuppressive therapy, even if the ASCO provisional clinical opinion considershe screening for patients at heightened risk for chronic HBV infection or if undergoing highly immunosuppressive therapy, as hematopoieticell transplantation and regimens including rituximab. Several meta-analyses support the prophylactic role of lamivudine in preventing HBVeactivation. Most of studies evaluated retrospectively or, if prospectively designed, compared the effect of prophylactic antiviral therapygainst historical controls.
∗ Corresponding author at: Unit of Clinical and Translational Research, Division of Medical Oncology, Department of Oncology and Hematology, Largoarozzi 1, Ospedali Riuniti Bergamo, 24128 Bergamo, Italy. Tel.: +39 035 269853; fax: +39 035 266849.
M. Mandalà et al. / Critical Reviews in Oncology/Hematology 87 (2013) 12–27 13
onclusion: Screening for HBV should be considered before chemotherapy. Prophylaxis with lamivudine can reduce the incidence of HBVeactivation as well as HBV-related morbidity and mortality. Unsolved issues include the role of antiviral agent with higher potency and lessesistance, how to monitor patients for reactivation and when to stop prophylaxis.
Hepatitis B is a major health problem worldwide with arevalence that varies according to geographic area [1]. It haseen reported that about 2 billion people show serological evi-ence of prior or current hepatitis B virus (HBV) infectionnd among those 350–380 million are chronic carriers. Beforehe introduction of vaccination programs, 20% and <1%f the population in the Asia-Pacific region and Australia,espectively, were hepatitis B surface antigen (HBsAg) pos-tive [1–3]. Although the incidence of acute HBV infectionas declined significantly as a result of universal infant vac-ination in the United States and in Western Europe, chronicnfections are still prevalent in these countries due to severalactors, including the immigration from areas where HBV isndemic, perinatal transmission, transmission among house-old contacts, and risk behaviors.
In regions with low prevalence like North America andestern Europe infection leads to acute HBV-related dis-
ase more often in the adolescent and adult population andymptoms include jaundice and nausea.
Chronic hepatitis B is defined as HBsAg > 6 months withr without sustained increase in aminotransferase. Up to 20%f the chronic persistent hepatitis cases progress to cirrhosis3].
The natural course of chronic HBV infection is deter-ined by the interplay between virus replication and host
mmune responses, and the outcome of chronic HBV infec-ion acquired early in life can be generally divided into threeistinct phases: immune tolerance phase (high viral loads,ormal serum ALT levels, and near-normal liver histology),mmune clearance phase (hepatitis B e antigen (HBeAg)-ositive, fluctuating serum ALT levels, and fluctuating serumiral loads), and low-replication phase (HBeAg negative,iral load < 4 log 10/ml, and normal ALT levels) [4].
There are 3 virological features for HBV carriers: activearrier, inactive carrier, anticore or anti-HBc (antibody toepatitis B core antigen)-positive (Table 1).
It is well understood that HBV persists for decades inatients following recovery from acute hepatitis B infectionuring which it is controlled by the immune system. Becausef this interaction, situations that lead to immunosuppressionn patients with chronic HBV infection may alter the naturalistory of this infection and give rise to the phenomenon ofeactivation.
There is not a uniform definition of reactivation in dif-erent guidelines, however, one that is commonly used ishe following: the presence of hepatitis as suggested by an
hot
LT > 2 ULN in combination with either an abrupt rise inBV replication of 1 log10 or an absolute value greater than0,000 IU/ml [4]. Both events occur in a patient with a pre-ious inactive HBV infection (an inactive carrier state or aatient with resolved hepatitis) [4]. HBV reactivation canccur in situations in which HBV replication increases; theost common causes of HBV reactivation are the immuno-
uppression regimens adopted in solid organ transplantation,hemotherapy for onco-hematological diseases and immu-osuppressive drugs used in the treatment of autoimmuneiseases [5–10].
During the immunosuppression phase there is a sharpncrease in viral replication and progressive infection of aarger number of hepatocytes. After reconstitution of themmunocompetence, the immune system reactivates againsthe infected hepatocytes and a severe hepatitis episode canevelop. In most cases reactivation occurs during this recov-ry phase from immunosuppression, one week to 3 monthsfter discontinuation of cytotoxic chemotherapy or immu-osuppressive agents and less frequently at the time of thenhanced replication during massive immunosuppression3].
In HBV carriers (occult or overt) the following virologicalvents should be considered as clinically relevant:
1) in anti-HBc subjects the re-emergence of HBsAg (serore-version);
2) in inactive carriers the appearance of a significant viremia(≥20,000 IU/ml) (reactivation), as this is frequently asso-ciated with liver damage due to HBV;
3) in active carriers the persistence of a significantviremia (≥20,000 IU/ml in HBeAg positive patients and>2000 IU/ml in HBeAg negative subjects with chronichepatitis) (activity), as this is frequently associated withprogression of liver damage due to HBV;
4) in all the virological categories (whether or not duringprophylaxis or therapy with antivirals), the increase inat least one logarithm of HBV DNA, compared to itsnadir, reconfirmed in two consecutive serum tests duringmonitoring (virologic breakthrough) [7].
The importance of reactivation of hepatitis B rests on itsotential severity and the ease of its prevention with pro-hylactic oral antiviral therapy. The clinical features of HBVeactivation vary from asymptomatic hepatitis to fulminant
epatic failure leading to death [3]. The delayed recognitionf reactivation and its complex virological and biological fea-ures can often cause clinical consequences. There is a need
14 M. Mandalà et al. / Critical Reviews in Oncology/Hematology 87 (2013) 12–27
Table 1Virological categories.
Active carrier Inactive carrier Anti-HBc positive (anticore)
Virological categoriesHBsAg Positive Positive NegativeHbeAg Positive or negative Negative NegativeAntiHBs Negative Negative Positive or negativeAntiHBc Positive Positive PositiveHBV DNA serum 2000–20,000 IU/ml <2000 IU/ml Negative (>90%)ALT Persistently or intermittently increased Persistently normal Persistently normalHL
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BV DNA tissue Positive
iver damage Yes (>90%)
or a wider awareness of reactivation of hepatitis B, when itccurs and how it should be prevented or managed.
This review summarizes the recent advances in this areaith regards to the incidence and risk factors of HBV
eactivation as well as the prevention and management inancer patients receiving cytotoxic chemotherapy for solidnd hematologic tumors.
For this purpose we performed an extensive “Med-ine” and Cancerlit literature review (1975–2012). Variousombinations of search terms were used depending onhe requirements of the database being searched. Theseerms included “hepatitis B virus” or “HBV” in com-ination with “immunosuppressed cancer patients” andincidence”, “pathogenesis”, “management” “primary pro-hylaxis”, “lamivudine”, “guidelines”, “reactivation”. Inddition, we researched manually all relevant review arti-les and the references of the retrieved papers. Finally,rials were excluded if relevant data could not bextracted.
. Incidence and risk factors of hepatitis Beactivation
Because serial HBV DNA monitoring is not widely per-ormed in patients receiving chemotherapy outside the settingf clinical trials, the recorded incidence of HBV reactivations likely to have been underestimated in many studies. Indeed,ne trial demonstrated that using the above definition ofeactivation hepatitis with conventional monitoring of HBVNA [i.e. at the time of alanine aminotransferase (ALT)
ise], the incidence of HBV reactivation was 24% in chronicarriers of HBV receiving chemotherapy for breast cancer,hereas with serial HBV DNA monitoring, 41% of patientsere identified as having HBV reactivation [11].Chemotherapy is highly immunosuppressive and may
ause flares of HBV in people who carry HBsAg in theirerum [3]. Flares can occur despite normal serum ALT lev-ls before chemotherapy is started [12–14] and may lead toigh HBV-related morbidity and mortality [15]. Since cancer
s an important leading cause of death, a large proportion ofhe population may undergo chemotherapy during their life-ime [7]. Therefore, even with a relatively low prevalence ofhe HBsAg carrier state, prevention of chemotherapy-induced
f
n
Positive PositiveNo (>90%) No
BV reactivation is an important medical problem and a pub-ic health concern. The problem is more critical in areas ofhe world where HBV infection is endemic [16,17].
Rituximab is a human-mouse chimeric monoclonal anti-ody that targets the B-cell CD20 cell surface proteinnd has become essential for the treatment of B-cellon-Hodgkin’s lymphoma [18–20]. Rituximab has beenound to induce durable B-cell depletion. Although lysisf HBV-infected hepatocyte killing is mainly mediatedy CD8-cytotoxic T-cell immunity, B cells may also acts antigen-presenting cells and prime cytotoxic T-cell-pecific responses in HBV infection [21–24]. Increasingvidence has linked rituximab to viral infections includ-ng herpes simplex virus, cytomegalovirus, parvovirus19, adenovirus [25]. Moreover, the pathophysiology of
ituximab-induced viral infections is unclear. The mecha-ism underlying HBV reactivation that follows rituximabreatment is likely to be more complex than simple B-cellepletion.
Stasi et al. [26] demonstrated that rituximab treat-ent leads to significant changes in T-lymphocyte activity,
ncluding increased Th1/Th2 and Tc1/Tc2 ratios, increasedxpression of Fas ligand on Th1 and Th2 cells, and expan-ion of oligoclonal T cells. A role for the importance of Bymphocytes in HBV reactivation may also be in part relatedo reduction of anti-HBV antibodies [i.e. HBsAb (hepatitis Burface antibody)-positive] caused by rituximab and the asso-iated host immunity balance. Tsutsumi et al. [27] showedhat despite serum immunoglobulin levels remained constanthrough treatment, HBsAb titers significantly decreased withituximab therapy. However, rituximab induces profound androlonged B-cell depletion binding the CD20 antigen, whichs expressed not only on neoplastic B cells but also onormal B lymphocytes. As B lymphocytes act as antigen-resenting cells for CD8-positive cytotoxic T cells that limithe expansion of HBV infection in hepatocytes, depletionf B lymphocytes by rituximab may result in defective T-ell responses to HBV, thereby allowing replication of theirus. Use of corticosteroids in many chemotherapy proto-ols may also play a role in the expansion of HBV, becauseBV-DNA contains a glucocorticoid response element that
isolone treatment increases levels of HBsAg, anti-HBc, and
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BV DNA in hepatocytes and decreases T-cell function. withdrawal of prednisolone means an intense rebound in
ytotoxic T-cell function that coincides with a surge in serumminotransferases and a decrease in the level of HBsAg andBV DNA. Immunosuppression is thought to enhance viral
eplication with a subsequent spread in hepatocyte infection.n addition, corticosteroids may cause a direct reactivationf the latent HBV infection. The findings of corticosteroidesponsive element in HBV DNA and the demonstration thatlucocorticoids specifically activate HBV gene expression inultured human hepatocellular carcinoma cells lend supporto the direct reactivation theory. Sporadic retrospective clin-cal studies also indicate that steroid-free chemotherapeuticegimens reduce the risk of hepatitis flares of HBV carriers30].
.1. Oncologic patients
Yeo et al. [11], in a prospective study, reported HBsAgeropositive breast cancer patients treated with conven-ional chemotherapy. The main objectives were to investigatehether “serial HBV DNA monitoring” could improve theiagnostic accuracy of diagnosing HBV reactivation com-ared with conventional monitoring of HBV DNA (i.e. athe time of ALT rise). Overall 41 patients were studied.en developed HBV reactivation by conventional monitor-
ng criteria (24%), but with serial HBV DNA monitoring,even additional patients (17/41: 41%) were diagnosed whenncreased HBV DNA levels were detected before, but notoncomitant with, clinical hepatitis. Premature terminationf chemotherapy or delay in treatment schedules occurredn 71% of the patients who developed viral reactivation, asompared to 33% in those who did not develop the condition.
Furthermore lung and gastrointestinal cancer, as well asreast cancer patients treated with cyclophosphamide, vin-ristine, adriamicin, methotrexate and fluorouracil and foliniccid, respectively, are associated with the occurrence ofeactivation, as reported from several diverse case studies,anging between 20% and 40% [31–33]. The highest rates ofBV reactivation have been reported in patients with breast
ancer (41%) [11].However, a prospective study highlighted that the degree
f immunosuppression as a result of the treatment could be more significant factor than the type of malignancy per sen the development of HBV reactivation [34].
In breast cancer patients receiving conventional cytotoxichemotherapy, Yeo et al. identified treatment with anthra-yclines as well as steroids and a detectable HBV DNAviral load) prior chemotherapy as main risk factors for HBVeactivation [34]. It must be noted that different studies havepplied different assays in measuring viral load, and this lackf standardization may have limited the correct understanding
f the problem [34].
Jang et al. have shown that transarterial chemo-ipiodolization (TACL) can reactivate HBV, and HBeAg-ositive hepatocellular carcinoma (HCC) patients receiving
n(Md
ology/Hematology 87 (2013) 12–27 15
ACL should be closely monitored for HBV reactivation35]. Among 83 patients undergoing TACL, HBVeactivation occurred in 28 (33.7%) patients, and HBeAgeropositivity was the only independent predictor of HBVeactivation. Three (10.7%) of them died of hepatic decom-ensation resulting from HBV reactivation. The authors havelso evaluated the efficacy of preemptive lamivudine ther-py in reducing hepatitis due to HBV reactivation in patientsith HCC undergoing TACL. A total of 73 consecutive HCCatients undergoing TACL were prospectively and randomlyssigned to receive lamivudine 100 mg daily from the startf TACL (preemptive group) or not (control group). Duringhe study, 11 (29.7%) of 37 patients in the control group and
(2.8%) of 36 patients in the preemptive group developedepatitis due to HBV reactivation. In addition, there wereignificantly more incidences of overall hepatitis and severerade of hepatitis in the control group. At multivariate Coxegression model, a baseline HBV DNA level of more than04 copies/ml was the only independent predictor of hepatitisue to HBV reactivation during TACL. In conclusion, in thistudy, preemptive lamivudine therapy demonstrated excel-ent efficacy in reducing hepatitis due to HBV reactivationnd hepatic morbidity during TACL [35].
.2. Hematological patients
Approximately 70–80% of malignant lymphomas are of cell origin, and >90% of B cell lymphomas expressD20 on the cell surface. CD20 is an appropriate targetolecule because it is not shed, modulated or internal-
zed. The introduction of rituximab into the therapeuticegimens has dramatically improved the prognosis of CD20-ositive lymphoma patients, but it has been associatedith HBV reactivation. Re-initiated HBV replication and
ncreasing levels of serum HBV-DNA have been reportedollowing systemic chemotherapy, especially those involv-ng rituximab-containing regimens, even in patients withesolved HBV infections [21]. In a multi-institutional phaseI trial for patients with relapsed or refractory B cell lym-homa, rituximab was shown to almost completely depleteormal mature B cells for an average period of 6–9 months36]. Recovery to normal levels may take 9–12 months.
Before rituximab, 24–53% of HBsAg-positive patientsn cancer chemotherapy experienced HBV reactivation.ccordingly, Yeo and Johnson [5] reported that HBV
eactivation occurred in 24% of HBsAg-positive lymphomaatients who received systemic chemotherapy. Lok et al. [9]eported reactivation in 48% HBsAg-positive patients withalignant lymphoma following systemic chemotherapy. Lau
t al. [37] conducted a randomized trial in 30 HBsAg-positiveymphoma patients either receiving or not receiving anti-viralrug prophylaxis during systemic chemotherapy. They found
o reactivation in patients receiving prophylaxis, but 8 of 1553%) patients without prophylaxis had HBV reactivation.
ore recently, Pei et al. [38] reported an extremely high inci-ence of HBV reactivation in HBsAg-positive lymphoma
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6 M. Mandalà et al. / Critical Reviews
atients receiving rituximab-containing chemotherapy.ithout prophylaxis in this setting, HBV reactivation
ccurred in 8 of 10 (80%) patients.Several trials have considered hepatitis reactivation with
ituximab.In the study by Yeo on HBsAg-negative/anti-HBc-positive
iffuse large B-cell patients, the objectives were to determinehe rate of HBV reactivation in patients treated with rituximabontaining chemotherapy and to compare the reactivationate with the rate of patients treated with conventionalhemotherapy without rituximab. The findings revealed thathe incorporation of rituximab was significantly associatedith the development of HBV reactivation [21].In this study on HBV reactivation in 80 HBsAg-
egative lymphoma patients receiving R-CHOP (ritux-mab, cyclophosphamide, doxorubicin, vincristine andrednisolone)-like or CHOP-like regimens, three importantisk factors were identified, namely, male gender, absencef anti-HBs at diagnosis of lymphoma and the use of rit-ximab [21]. HBV reactivation occurred in five (6.25%) ofhese patients, with four receiving antivirals and one patientying of hepatitis. All 5 patients were anti-HBc-positive andBsAb-negative and had received R-CHOP. Thus, of 21
nti-HBc-positive patients receiving R-CHOP, five (23.8%)howed HBV reactivation. Therefore, not only HBsAg-ositive patients, but also some HBsAg-negative patients,ncluding anti-HBc-positive and/or anti-HBs-positive and/orBV-DNA-positive patients, should be considered at high
isk for HBV reactivation following rituximab plus-steroidombination chemotherapy.
Also, Hui et al. [39] reported that of 244 HBsAg-negativeymphoma patients receiving systemic chemotherapy, eight3.3%) developed HBV reactivation and all of them wereither anti-HBc-positive and/or anti-HBs-positive. Moreover,he incidence of HBV reactivation in the rituximab-plus-teroid combination group was higher, namely, 12.2% (6/49atients) than that in other combination therapy groups, inhich it was only 1.0% (2/195 patients). Multivariate anal-sis demonstrated that rituximab-plus-steroid combinationhemotherapy was a risk factor for HBV reactivation inBsAg-negative patients.Less is known about other monoclonal antibodies includ-
ng Alentuzumab (anti-CD52) and Infliximab (anti-TNF).onetheless, it is known that all these agents can lead torofound and long-lasting immune-suppression, which maye responsible for post-treatment HBV reactivation [40,41].steve et al. indicated that patients with Crohn’s disease whore candidates for infliximab therapy should be tested forepatitis B serological markers before treatment and consid-red for prophylaxis of reactivation using antiviral therapy ifositive [42].
Furthermore, the risk of HBV reactivation tends to be
ore frequent in patients with hematological malignancies
n particular with lymphomas [14,43,44] and in those under-oing hematopoietic stem cell transplantation (HSCT) [45],ue to the fact that these patients are often subject to intense
Heh(
ology/Hematology 87 (2013) 12–27
yelosuppressive treatment regimens and these malig-ancies, per se, are often associated with an immune-ompromised status.
In HBsAg positive patients receiving intensive cytoreduc-ive therapy and high- dose chemotherapy prior to HSCT, theBV reactivation rates are on average about 50% [45].In patients undergoing autologous hematopoietic cell
ransplantation (HCT), the risk of hepatitis flare due to HBVeactivation was found to be as high as 33 fold in HBsAg-ositive than in HBsAg-negative patients [12]. FurthermoreBsAg-positive patients with detectable serum HBV DNAefore HCT (on Digene assay) had a nine-fold higher riskf hepatitis due to HBV reactivation than HBsAg-positiveatients with no detectable serum HBV DNA. A high HBVNA level (>105 copies/ml) has been reported to be one of
he most important risk factors for HBV reactivation.Actually, Hui et al. examined the serological and liver
elated outcome of 803 consecutive patients who receivedllogeneic HSCTs, with a median follow-up period of 83onths (range, 0.5–155 months). Late HBV-related hepatitis
ccurred in 2 of the 721 HBsAg-negative recipients comparedith 16 of the 82 HBsAg-recipients after HSCT (0.3% versus9.5%; P < 0.001 by log-rank). The study showed that long-erm hepatic complications occur in a significant proportionf HBsAg-positive patients after HSCT [45].
Moreover, the incidence, risk factors and course ofBV reactivation after HSCT in HBsAg-negative/anti-HBc-ositive recipients are not well known (Table 2).
.3. HBV reactivation in anti-HBc-positive patients
Reactivation of HBV due to chemotherapy mainly occursn HBsAg-positive patients but can also be observed inerologically recovered HBsAg-negative patients with anti-Bc positivity and/or anti-HBs positivity [21,38], but thisccurs less commonly than in patients who are HBsAg-ositive. However, with the recent increased use of rituximab21], reports of HBV reactivation after treatment with thisgent in patients with resolved HBV infections have alsoncreased. Based on case series, nearly 20% of patients diedf hepatic failure. HBV reactivation has also been associatedith HSCT in patients with hematologic malignancies with
esolved HBV infections [46]. The discovery that HBV canersist for decades after clinical recovery from acute hep-titis B, despite the presence of serum HBsAb, has providednsights into the pathogenesis of HBV reactivation in patientsho are HBsAg negative prior to chemotherapy or immuno-
uppressive therapy [47,48]. The persistence of HBV, decadesfter clinical recovery, suggests that recovery from acute hep-titis B infection does not represent a complete eliminationf the virus. HBV replication has been shown to persist inhe liver and in peripheral blood mononuclear cells of most
BsAg negative/anti-HBc positive patients who have appar-
ntly cleared HBV infection. These patients are referred to asaving occult HBV infection. By definition, occult hepatitis BOBI) is characterized by the persistence of HBV-DNA in the
M. Mandalà et al. / Critical Reviews in Oncology/Hematology 87 (2013) 12–27 17
Table 2Trials on the HBV reactivation in hematopoietic stem cell transplantation.
Study (reference) Number of patients Duration of follow up,months
% HBV reactivationor acute hepatitis
Lau [12] 13723 HBsAg+ (A)37 HBsAg− (B)77 HBsAg or antiHBs−(C)HBVDNA+: 10 (D)HBVDNA−: 109 (E)
Abbreviations: HBsAg: hepatitis B surface antigen; HBV-DNA: hepatitis B virus DNA; anti-HBc: antibody to hepatitis B core antigen; anti-HBV therapy:anti hepatitis B virus therapy.Definitions: Lau [12] – A: HBsAg positive patients without prophylaxis; B: HBsAg negative patients without prophylaxis; C: HBsAg negative or antiHBsnegative patients without prophylaxis; D: HBVDNA positive on Digene assay; E: HBVDNA negative on Digene assay.Hui [45] – A: HBsAg− patients; B: HBsAg+ patients.Moses [41] – A: anti-HBc+ recipients who received lamivudine prophylaxis; B: anti-HBc− recipients who did not receive lamivudine prophylaxis.H ho receG HBsA
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ui [79] – A: patients who did not receive anti-HBV therapy; B: patients wiaccone [80] – A: anti-HBc+ patients; B: HBsAg+ patients; C: anti-HBc−
iver tissue (and in some cases also in the serum) in absence ofBsAg [48]. According to the HBV serological profile, OBIay be antibody (anti-HBc alone or together with anti-HBs)
ositive (seropositive OBI) or antibody negative (seroneg-tive OBI). The molecular basis of the occult infection istrictly related to the conversion of the 3 Kb relaxed circularenome into a covalently closed-circular DNA (cccDNA), aong lived HBV replicative intermediate that persists in theell nuclei as a stable chromatinized episome and that servess template for gene transcription. The stability and long-termersistence of viral cccDNA molecules together with the longalf-life of hepatocytes imply that HBV infection, once itas occurred, may possibly continue for life. Thus, the occultnfection appears to be mostly due to a strong suppression ofiral replication and gene expression affecting viruses, whoseenetic variability is comparable to that of HBV strains fromndividuals with “overt” chronic HBV infection [48].
OBI may impact in several different clinical contexts
ncluding the risk of HBV transmission with transfusionr transplantation, and endogenous viral reactivation. Theold standard test for detection of occult infection is the
v4h
ived anti-HBV therapy.g− transplanted from HBsAg+ donors patients.
mplification of HBV DNA. However, the anti-HBc rep-esents a qualified candidate as a surrogate for DNAmplification, or for increasing overall sensitivity whenssessing the risk of occult hepatitis in peripheral blood. Theisk of occult hepatitis associated with anti-HBc seropositi-ity has been demonstrated extensively, and the presence ofnti-HBc can be considered a sentinel marker occult HBVnfection [49].
Occult HBV infection is a world-wide diffused entity,lthough its distribution may reflect the general prevalence ofhe HBV in the various geographic areas and in the variousopulations. There is a fairly general agreement in consider-ng hepatitis C virus (HCV) infected patients as the categoryf individuals with the highest prevalence of occult HBV50]. In particular, HBV DNA is detectable in about one-thirdf HBsAg negative HCV carriers in the Mediterranean basin,nd this prevalence is even higher in Far East Asian countries48]. Moreover, a high prevalence has been reported in indi-
iduals at high risk of parenteral-transmitted infections, with5% in intravenous drug addicts in Baltimore and 51% inemophiliacs in Japan [48]. On the contrary, the studies
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erformed up to now on hemodialysis patients provide widelyivergent results, reporting a prevalence of occult HBV thatanges from 0% to 36% [51,52]. The published prevalence inIV positive individuals ranges from 0% to 89% [53]. Among
he blood donors, this OBI appears to have a rare occurrencen the Western world, whereas it is frequently detected in theeveloping countries [48]. With regard to the general pop-lation, in a study evaluating the occult HBV prevalence inBsAg negative residents of a Canadian Inuit community,inuk et al. detected HBV DNA in 18% of anti-HBc pos-
tive subjects and in 8% of HBV seronegative individuals,espectively [54], whereas Kim et al. found occult HBV in1 of 195 (16%) Korean HBV/HCV negative healthy sub-ects [55], and Hui et al. detected occult HBV genomes in 19ut of 124 (15.3%) healthy hematopoietic stem cell donorsrom Hong Kong [56].
In anti-HBc-positive patients immunosuppression canllow active viral replication to start again, resulting in thee-emergence of HbsAg. This clinical scenario is referred tos reverse seroconversion or seroreversion. Thus, immuno-uppressive therapy may result in HBV reactivation, evenn individuals who are anti-HBc and/or anti-HBs posi-ive. The immunocompromised state due to malignancy andhemotherapy may result in enhanced replication of exist-ng low levels of HBV, which leads to rapid destruction ofnfected hepatocytes upon the recovery of the immune func-ion, resulting in HBV-related hepatitis flare.
Even though Yeo et al. did not define varying degreesn the level of immunosupression, they reported the inci-ence of seroreversion in HBsAg-negative diffuse large-cell
lymphoma patients treated with chemotherapy (cyclophos-hamide, doxarubin, vincristine, and prednisone) whoeceived rituximab versus those who did not receive ritux-mab [21]. Eighty patients were HBsAg negative. Forty-sixatients (44.2%) were HBsAg negative/anti-HBc positive;5 of these patients were treated with CHOP, and none hadBV reactivation. In contrast, among the 21 patients treatedith R-CHOP, five developed HBV reactivation, includingne patient who died of hepatic failure. Exploratory analysisdentified male sex, absence of anti-HBs, and use of ritux-mab to be predictive of HBV reactivation. Hence, amongBsAg-negative/anti-HBc-positive DLBCL (diffuse large B
ell-lymphoma) patients treated with R-CHOP, 25% devel-ped HBV reactivation.
Koo et al. showed that the rate of HBV reactivation isow in patients who are HBsAg negative/anti-HBc positiveeceiving rituximab-based combination chemotherapy with-ut concomitant antiviral prophylaxis (4%). However, elderlyatients, particularly those without anti-HBs, seemed partic-larly at risk [57].
Viganò et al. evaluated a total of 50 HBsAg-negative/anti-Bc-positive HSCT recipients with onco-hematological
iseases. During 17 months of follow-up, six (12%) patientsad seroreverted to HBsAg, 7–32 months after HSCT, with- and 5-year cumulative rates of 13% and 22%. Patientsith chronic onco-hematological disease and long-lasting
na
f
ology/Hematology 87 (2013) 12–27
mmunosuppression following HSCT had a higher risk ofBsAg seroreversion independently of serum HBV DNA
evels at HSCT. HBsAg-negative/anti-HBc-positive HSCTecipients with chronic onco-hematological disease carry aignificant risk of HBsAg seroreversion and HBeAg-positivehronic hepatitis B, independently of serum levels of HBVNA at transplantation [58] (Table 3).The increased risk associated with corticosteroids is
hought to be due to both the immunosuppressive effect andirect stimulation of viral replication via a glucocorticoidesponsive receptors on HBV surface [59].
All the available data clearly suggest that reactivation canccur at any time during chemotherapy or after it, duringhe recovery phase of the immune system’s reconstitution.his can lead to poor outcomes, hepatic flares, liver fail-re, and death. Given the significant risk of viral reactivationnd its life-threatening sequelae, monitoring and prophylac-ic strategy have been recommended for preventing from theeactivation of HBV during and after chemotherapy.
It is important to identify these patients accurately so thatffective prophylaxis or oral antiviral therapy can be promptlynitiated.
. HBV screening before chemotherapy ormmunosuppressive therapy
Most guidelines endorse recommendations that are ingreement [7,60–64]: all patients with cancer who are abouto undergo potentially immunosuppressive therapy should becreened for HBsAg, anti-HBc, and HBsAb.
A concomitant exhaustive evaluation of liver functionaltatus and staging should be adopted. The choice betweenrophylaxis and treatment of HBV depends on the definitionf the combination of virological and hepatological statusf the patient [60,61]. Recommendations from ASCO [62]re state that only patients who undergo “highly” immuno-uppressive regimens (i.e., stem cell transplants or treatmentith rituximab) and patients “at risk” for HBV should be
ested, and screening should only be for HBsAg and anti-Bc. Although there is agreement on the importance of
ntiviral prophylaxis, ASCO does not advocate the use ofll 3 screening tests. The ASCO provisional clinical opinionecommends that oncologists screen patients at risk for HBVnfection, thus taking the time to find out if patients show riskactors for HBV infections.
Scottish Viral Hepatitis group and the Scottish diagnosticirology group recommend to screen all patients undergoinghemotherapy for hematological malignancies for HBsAg,nti-HBc [63].
The European Association for the Study of the Liverecommends that all candidates for chemotherapy and immu-
osuppressive therapy should be screened for HBsAg andnti-HBc prior to initiation of treatment [64].
The Italian Association for the Study of the Liver [7],or patients with solid tumors, recommends HBsAg only as
M. Mandalà et al. / Critical Reviews in Oncology/Hematology 87 (2013) 12–27 19
Table 3Trials assessing the implication of anti-HBc positivity.
Study (reference) Number of patients Diagnosis Treatment Reactivation (%)
Abbreviations: Anti-HBc: antibody to hepatitis B core antigen; HBsAg: hepatitis B surface antigen; HSCT: Hematopoietic Stem Cell Transplant.Definitions: Matsue [29] – A: anti-HBc+ patients; B: anti-HBc− patients.K clophosB TranspJ phosph
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oo [57] – A: patients who received R-CHOP chemotherapy (rituximab, cyorentain [82] – A: patients who received HSCT (Hematopoietic Stem Cell
i [84] – A: patients who received R-CHOP chemotherapy (rituximab, cyclo
asal screening, because the clinical significance of isolatenti-HBc positivity in patients with solid tumors is unclearnd there are no clinical evidences of higher risk of HBVeactivation in patients with isolated anti-HBc positivity inomparison with patients without serum markers of HBVnfection.
Screening clinical recommendations of several interna-ional associations are reported in Table 4. HBsAg-positiveandidates for chemo- and immunosuppressive therapyhould be tested for HBV DNA levels, although in the lit-rature few studies have been conducted to evaluate the usef HBV DNA as a screening before chemotherapy [32,65].oreover, the clinical evidence does not provide enough
nformation to determine the optimal frequency and durationf such HBV-DNA monitoring.
Recently, aiming at investigating the current practicemong oncologists regarding HBV screening and antiviralrophylaxis in candidates for chemotherapy, a survey wasent to the American Medical Association-registered onco-ogists [66]. Of the total respondents, 20% reports nevercreening for HBV prior to initiating therapy, 38% screens ifhe patient shows risk factors or a history of hepatitis, 30%creens if liver tests are abnormal, 11% screens occasionallyn a random basis and 13% screens every patient for HBV.
A recent paper highlighted concerns regarding HBVcreening in oncologic patients and concluded that universalcreening for hepatitis B virus (HBV) is not cost-effectiven patients with solid tumors who undergo chemotherapy67]. Testing may be adopted if it is limited to “selectedatient subpopulations” or if it is simplified. Using anncremental cost-effectiveness ratio threshold of $50,000Australian dollars, which are nearly equivalent to Amer-
can dollars) per life-year saved, the authors showed thatniversal HBV screening “was not cost-effective” for adju-ant treatments ($88,224/life-year; 13% probability of beingost-effective), palliative treatments ($1,344,251/life-year;
ie
b
phamide, doxorubicin, vincristine and prednisolone).lant); B: patients who received rituximab.amide, doxorubicin, vincristine and prednisone).
%), or all patients ($149,857/life-year; 1%). However, thistudy did not consider important costs such as hospital-zation, time lost from work, treatment delays related toepatitis reactivation, and other factors. Furthermore focus-ng the screening on “selected patient subpopulations,” whichefers to patient ethnicity may be potentially dangerous sincehe lack of large population-based studies and the currentrevalence of HBV reactivation in patients undergoing cancerreatment is unclear. Clearly, in areas of high HBV endemicityll patients should be screened for HBsAg and anti-HBc prioro immunosuppressive chemotherapy. Recently, Zurawskat al. developed a decision model to compare the clinicalutcomes and costs of three screening strategies for patientsith lymphoma before R-CHOP: screening all patients forbsAg, screening patients identified as being at high risk forBV reactivation and screening no one. The results shown
hat screening all patients for HBV reduces the rate of HBVeactivation (10-fold) and is less costly than screening onlyigh-risk patients or screening no patients [68]. Furthermore,lthough there are not large population based studies evalu-ting the role of screening in cancer patients, it’s importanto highlight that the cost of screening for HBsAg is relativelyow whereas the clinical consequences of reactivation can beife-threatening.
. Prophylactic drugs
Nucleoside analogs (NASs) have become widely acceptedor prophylaxis of reactivation of HBV in clinical practice.
There are 5 nucleos(t)ides analogs (NASs) poten-ially currently available for hepatitis B carriers receiving
mmunosuppressive therapy: lamivudine, adefovir-dipivoxil,ntecavir, telbivudine and tenofovir.
Lamivudine is a pyrimidine nucleoside analog that inhibitsinding of nucleosides to the HBV polymerase [69,70].
20 M. Mandalà et al. / Critical Reviews in Oncology/Hematology 87 (2013) 12–27
Table 4Screening for hepatitis B in cancer patients receiving immunosuppressive therapy.
Scientific society Recommendation
Oncologic Hematologic
AASLD [61] HBsAg, anti-HBc HBsAg, anti-HBcEASL [64] HBsAg, anti-HBc HBsAg, anti-HBcCDC [85] HBsAg, anti-HBc, HBsAb HBsAg, anti-HBc, HBsAbScottish Liver Society [63] None HBsAg, HBcAbNIH Consensus [86] HBsAg HBsAgItalian Guidelines [7] HBsAg HBsAg, anti-HBc, HBsAbASCO [62] Only patients who undergo certain “highly” cytotoxic or immunosuppressive therapies (i.e., stem cell
transplants or treatment with rituximab) and patients “at risk” for HBV (HBV infection or prior exposureto HBV): HBsAg, anti-HBc
Abbreviations: HBsAg: hepatitis B surface antigen; anti-HBc: antibody to hepatitis B core antigen; HBsAb: hepatitis B surface antibody.AASLD [61]: American Association for the Study of Liver Diseases, www.aasld.org; EASL [64]: European Association for the Study of Liver Diseases,w w.cdc.gN ih.gov;w
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ww.easl.eu; CDC [85]: Centers for Disease Control and Prevention, wwIH Consensus [86]: National Institute of Health consensus, consensus.nww.apasl.info; Canadian Guidelines [88]: www.hepatology.ca.
enerally, lamivudine is effective at lowering HBV viral load.owever, HBV becomes resistant to lamivudine, with therevalence of its resistance approaching 70% in four years.urthermore, the development of lamivudine resistance also
ncreases the likelihood of resistance to other antiviral agents,nd may compromise the response to other drugs, includingdefovir, entecavir and telbivudine.
Adefovir dipivoxil is a purine nucleotide analog [71]. It isot a highly potent agent and its slow antiviral activity canelay, but not achieve a complete viral suppression in theajority of patients, this way increasing the risk for develop-
ng viral resistance.Entecavir is a selective guanosine analog and is the most
otent inhibitor of HBV DNA replication currently avail-ble [70,72]. It can suppress viral replication more effectivelyhan lamivudine in treatment-naïve patients in both HBeAg-ositive and HBeAg-negative subjects.
Telbivudine is a pyrimidine nucleoside analog with potentntiviral efficacy against HBV [73]. Telbivudine suppressesBV replication more effectively than lamivudine. It is moreotent than lamivudine and can be used in patients with highiral loads. However, as with lamivudine, inadequate sup-ression of the virus in cases of high viral load is associatedith development of significant rates of resistance [73].Tenofovir is a purine analog, interferes with the action of
he DNA polymerase, which is involved in the formation ofiral DNA [74].
.1. Clinical trials in oncology and hematology setting
Over the past decade, it has been recognized that HBVeactivation and its associated fatality during chemother-py can be prevented effectively by adopting a prophylactic
trategy. Lamivudine appears to be safe and cost-effective.he published experience in the prevention and treatment ofBV reactivation is almost entirely limited to lamivudine
Tables 5 and 6). A systematic review assessed the effect
bba
ov; ASCO [62]: American Society of Medical Oncology, www.asco.org; APASL [87]: The Asian Pacific Association for the Study of the Liver,
f preventive lamivudine on hepatitis B reactivation duringhemotherapy [69]. This research revealed that preventiveamivudine reduces the risk for HBV-related hepatitis by 79%r more. In addition, preventive lamivudine may reduce theisk for HBV-related hepatic failure and death in patients whoesult to be positive for HBsAg and receive chemotherapy.everal strategies employing lamivudine have been proposed
o deal with chemotherapy-induced HBV reactivation: pro-hylaxis, targeted prophylaxis and treatment of active HBVisease. In patients at high risk of HBV reactivation antivi-al prophylaxis therapy should be started pre-emptively priorr together with chemotherapy, since this reduces the risknd severity of reactivation hepatitis and allows chemother-py to be completed. The optimal duration of preventiveamivudine therapy has not been conclusively determined yet,lthough maintenance lamivudine for 6 months after discon-inuing chemotherapy has been recommended [9,14,75]. Thistrategy has been shown effective both demonstrated in lym-homa and breast cancer patients as well as in retrospectivend prospective trials [76,77]. Although lamivudine therapyeduces the risk, HBV reactivation and death remain a pos-ibility [21]. The efficacy of long-term lamivudine therapys limited by the appearance of antiviral resistance [3]. Forhese reasons, preventive use of recently available, potentnti-HBV agents (such as entecavir, telbuvidine, adefovir,nd tenofovir) might be preferable to further reduce the riskor morbidity and mortality in high-risk patients [78]. Theseewer agents, however, are more expensive than lamivudine,nd their long-term safety is less well defined. Large, prospec-ive, and well-designed randomized, controlled studies areeeded to address this issue. Although results of the researchynthesis provide important evidence that supports the usef preventive lamivudine in a chemotherapy setting, severalimitations exist. The clinical trials included were limited
y small sample sizes; heterogeneity of patient populations,aseline demographic characteristics or viral-host factors,nd type of chemotherapeutic regimens used; and variable
M. Mandalà et al. / Critical Reviews in Oncology/Hematology 87 (2013) 12–27 21
Table 5Trials on the prophylaxis of hepatitis B (HBsAg positive): solid tumors.
Study (reference) Number of patients Chemotherapy Duration of prophylaxis % HBV reactivationor acute hepatitis
Prospective randomized trialsLong [77] 42 Breast cancer
21 Lamivudine (A)21 No prophylaxis (B)
Anthracycline,anthracycline-taxanesbased
Day 1 to 2 months after CT A: 0%B: 28.6%P = 0.021
Jang [35] 73 HCC37 Lamivudine (A)36 No prophylaxis (B)
TACL Day 1 to 12 months after TACL A: 2.8%B: 29.7%P = 0.002
Prospective trial with historical controlYeo [76] 92 Breast cancer
31 Lamivudine (A)61 Historic control (B)
Anthracycline, nonanthracycline basedtaxanes
Day 1 to 2 months after CT A: 6.5%B: 31.1%P = 0.008
Yeo [89] 37 Nasopharyngealcarcinoma16 Lamivudine (A)21 Historic control (B)
Cisplatinum based Prior to and until 8 week after CT A: 0%B: 28.6%P = 0.027
Retrospective trialsDai [90] 11 Breast cancer Anthracycline-based Day 1 to 1 month after CT 0%Dai [91] 6 Breast cancer Anthracycline-based Day 1 to 1 month after CT 0%Yun [92] 131 Breast cancer
55 Lamivudine (A)76 No prophylaxis (B)
Anthracycline-based Day 1 to 2 months after CT A: 9%B: 33%
Sohn [93] 169 Breast cancer41 Lamivudine (A)128 No prophylaxis (B)
Anthracycline-based Day 1 to 2 months after CT A: 2.4%B: 14.1%
Nagamatsu [94] 17 HCC HBeAg+8 Lamivudine (A)9 No prophylaxis (B)
TACL NR A: 0/8B: 6/9
Abbreviations: HCC: hepatocellular carcinoma; TACL: transarterial chemo-lipiodolization using epirubicin (50 mg/m2) and cisplatin (60 mg/m2) in a mixtureof lipiodol (5–10 ml).Definition: Long [77], Jang [35], Yun [92], Sohn [93] and Negamatsu [94] – A: patients who received lamivudine; B: patients who did not receive prophylaxis.Y control
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eo [76] and Yeo [89] – A: patients who received lamivudine; B: historical
uration of treatment and follow-up, all of which may limithe overall treatment effects. Most studies were retrospec-ive cohort studies or prospective cohort studies that hadither a historical or a concurrent control group. Despitehese limitations, the treatment effect was in favor of pre-entive lamivudine therapy. Large, randomized, controlledtudies are needed to establish the exact duration of preventiventi-HBV therapy and to define the clinical role and efficacyf newer anti-HBV agents, such as entecavir, telbuvidine,defovir, and tenofovir.
.2. Management of immunosuppressed patients witholid tumors
In HBsAg positive patients is mandatory useful to evalu-te liver function tests (LFTs) and serum HBV-DNA levelsefore starting chemotherapy in order to differentiate activearrier from and inactive carrier (Fig. 1a, Table 7).
For active carriers therapy with more potent NASs (ente-
avir or tenofovir) is indicated, with the aim of controllinghe disease pre- and post-treatment.
For inactive carriers undergoing adjuvant or neo-adjuvanthemotherapy definite prophylaxis with lamivudine should
tmal
s who underwent chemotherapy without prophylactic lamivudine.
e adopted and should be continued for the entire treatmentnd for 6–12 months after the end of the chemotherapyTable 7). However, data are still insufficient to define theptimal duration of prophylactic antiviral therapy. Prema-ure withdrawal of lamivudine could lead to a rapid reboundf viral replication, resulting in HBV-related mortality. Onhe other hand, prolonged use of lamivudine in absence ofiral replication is not associated with an increasing likeli-ood of developing lamivudine-resistance HBV variants withMDD mutants. Many guidelines differ in the duration of
reatment, from at least 3 to 12 months after completionf chemotherapy. The European Association for the Studyf the Liver recommends that HBsAg-positive candidatesor chemotherapy and immunosuppressive therapy should beested for HBV DNA levels and should receive pre-emptiveASs administration during therapy regardless of HBV DNA
evels and for 12 months after cessation of therapy [64].he American Society of Clinical Oncology suggests that,hen evidence for chronic HBV infection is found, antiviral
herapy before and throughout the course of chemotherapyay be considered to reduce the risk of HBV reactivation,
lthough evidence from controlled trials of this approach isimited [62].
22 M. Mandalà et al. / Critical Reviews in Oncology/Hematology 87 (2013) 12–27
Table 6Trials assessing the role of prophylaxis for the prevention of hepatitis B: lymphoma.
Study (reference) Number of patients Chemotherapy Duration of prophylaxis Reactivation (%)
Treatment without rituximabRandomized trialsLau [37] 30
Lamivudine pre CT (A)Deferred lamivudineprophylaxis (B)
CHOP, COPCEOP, ABVD
A: Day 1 to 6 weeks after CT A: 0%B: 8 (53%)P = 0.002
Hsu [95] 51Lamivudine pre CT (A)Deferred lamivudineprophylaxis (B)
CHOP A: Day 1 to 2 months after CT A: 3 (11.5%)B: 14 (31%)P = 0.001
Yeo [21] 2415 Lamivudineprophylaxis (A)9 No lamivudineprophylaxis (B)
CHOP-R Day 1 until 8 weeks after CT A: 66.7%B: 55.5%
Abbreviations: CT: chemotherapy; CHOP: cyclophosphamide, doxorubicin, vincristine and prednisolone; CHOP-R: cyclophosphamide, doxirubicin, vin-cristine, prednisolone and rituximab; COP: cyclophosphamide, vincristine and prednisone; CEOP: cyclophosphamide, etoposide, vincristine and prednisone;ABVD: doxorubicin, bleomycin, vinblastine and dacarbazine; MOPP: mechlorethamine, vincristine, procarbazine and prednisone; MACOP: methotrexate,doxorubicin, cyclophosphamide, vincristine and prednisone; NR: not reperted; ACO: adriamycin, cyclophosphamide and vincristine; ICE: ifosfamide, carbo-platin and etoposide.Definition: Lau [37] and Hsu [95] – A: patients who received lamivudine pre-chemotherapy; B: patients who received deferred lamivudine prophylaxis.Idilman [96], Shibolet [97], Li [100] and Yeo [21] – A: patients who received lamivudine prophylaxis; B: patients did not receive prophylactic lamivudine.Persico [101] and Chen [102] – A: patients who received prophylaxis; B: patients did not receive prophylaxis.Li [103] – A: patients who received entecavir; B: patients who received lamivudine.
a Historic control; NR = not reported.
M. Mandalà et al. / Critical Reviews in Oncology/Hematology 87 (2013) 12–27 23
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For inactive carrier with advanced solid tumors undergo-ng palliative chemotherapy prophylaxis with lamivudine orther NASs should be continued for the entire treatment.
HBsAg negative patients should undergo liver enzymesonitoring every cycle of chemotherapy or every 1–3onths, since the low risk of reactivation in this group of
atients does not justify prophylaxis with lamivudine.If HBsAg repositivization occurs during chemotherapy a
escue-therapy with entecavir or tenofovir in order to pre-ent liver failure and to avoid the premature termination ofhemotherapy should be adopted.
.3. Management of immunosuppressed hematologic
atients
In HBV carriers receiving chemotherapy or immunosup-ressive therapy, the risk of reactivation is high, particularly
bic
able 7anagement strategy for immunosuppressed patients with solid tumors.
bbreviations: HBsAg: hepatitis B surface antigen; anti-HBc: antibody to hepatiti
f rituximab is given alone or in combination with steroids21]. All candidates for chemotherapy and immunosuppress-ve therapy should be screened for HBsAg and anti-HBc prioro initiation of treatment. HBsAg-positive candidates forhemo- and immunosuppressive therapy should be tested forBV DNA levels and receive prophylactic pre-emptive NASs
dministration during chemotherapy and for 6–12 monthsfter its cessation (Fig. 1b, Table 8), unless they have activeBV-related liver disease for which they would need life-
ong antiviral therapy regardless of their oncologic status.
.4. Unsolved issues in the current literature
The current published recommendations [7,60–64] areased on limited evidence [15,69]. Most of the stud-es evaluated retrospectively or, if prospectively designed,ompared the effect of prophylactic antiviral therapy to
6–12 months after the end of therapyUniversal prophylaxisa or monitoringand targeted prophylaxis (afterseroreversion HBsAg− → HBsAg+)
Abbreviations: HBsAg: hepatitis B surface antigen; anti-HBc: antibody to hepatitis B core antigen; HBV DNA: hepatitis B virus DNA.a High risk (hematology): chemotherapy with fludarabine, dose-dense regimens, allogenic Tx, autologous mieloablative Tx, induction of acute leukemias,
use of monoclonal antibodies (antiCD20, antiCD52): prophylaxis for 12–18 months.
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istorical controls. There are no large prospective trials eval-ating homogeneous cohort of patients and most of therials included patients treated with heterogeneous cytotoxicchedules. Furthermore, most of the trials are monocentric,esigned and conducted in specific geographic areas andbsolute benefit of prophylaxis not necessarily may bextended to patients treated in the Western world.
Finally the mortality related to the HBV reactivation is notenerally reported and this does not allow to clearly under-tand the real benefit of prophylaxis in terms of improvementf survival. Although the above mentioned meta-analysisemonstrated that preventive therapy with lamivudine mayeduce the risk of HBV reactivation and HBV-associatedorbidity and mortality, most of the included studies are
etrospective [69].Further unsolved issues include the role of antiviral agent
ith higher potency and less resistance, how to monitoratients for reactivation and when to stop prophylaxis. Toonclude, further prospective clinical trials comparing thefficacy of lamivudine versus other more potent antiviralgents such as entecavir, adefovir and tenofovir are needed.
. Conclusions
HBV reactivation in immunosuppressed cancer patientss a serious clinical problem for HBV carriers undergoinghemotherapy, because it may result in severe liver injurynd prevent completion of life-saving treatment of the under-ying malignant disease. Screening for HBV is requiredefore chemotherapy, and prophylactic antiviral therapy caneduce not only the incidence of HBV reactivation, but alsoBV-related morbidity and mortality. This potentially fatal
omplication may be prevented by the use of oral antiviraledication prior to start chemotherapy. Physicians should
e aware of this potentially life-threatening but preventableomplication, and closely monitor HBV carriers undergoinghemotherapy.
eviewers
Professor Alfredo Marzano, MD, University of Turin, Saniovanni Battista Hospital, Turin, Italy.
Professor Bertrand Coiffier, MD PhD, Centre Hospitalieryon Sud, Hematology Department, Pavillon Marcel Bérard,-69495 Pierre Benite Cedex, France.
Professor Ramazan Idilman, MD, Ankara University Fac-lty of Medicine, Department of Gastroenterology, Ankara,urkey.
Dr Jessica P. Hwang, MD, MPH, The University of Texas,D Anderson Cancer Center, 1515 Holcombe Blvd, Hous-
on, TX 77030, United States.
eferences
[1] Ganem D, Prince AM. Hepatitis B virus infection – natural his-tory and clinical consequences. New England Journal of Medicine2004;350:1118–29.
[2] Lavanchy D. Hepatitis B virus epidemiology, disease burden, treat-ment, and current and emerging prevention and control measures.Journal of Viral Hepatitis 2004;11:97–107.
[3] Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Managementof hepatitis B: summary of a clinical research workshop. Hepatology2007;45:1056–75.
[4] Liaw YF, Chu CM. Hepatitis B virus infection. Lancet2009;373:582–92.
[5] Yeo W, Johnson PJ. Diagnosis, prevention and management of hep-atitis B virus reactivation during anticancer therapy. Hepatology2006;43:209–20.
[6] Galbraith RM, Eddleston AL, Williams R, Zuckerman AJ. Fulmi-nant hepatic failure in leukaemia and choriocarcinoma related towithdrawal of cytotoxic drug therapy. Lancet 1975;2:528–30.
[7] Marzano A, Angelucci E, Andreone P, et al. Italian Associationfor the Study of the Liver. Prophylaxis and treatment of hepati-tis B in immunocompromised patients. Digestive and Liver Disease2007;39:397–408.
[8] Bird GL, Smith H, Portmann B, Alexander GJ, Williams R. Acuteliver decompensation on withdrawal of cytotoxic chemotherapy andimmunosuppressive therapy in hepatitis B carriers. Quarterly Journalof Medicine 1989;73:895–902.
[9] Lok AS, Liang RH, Chiu EK, et al. Reactivation of hepatitis Bvirus replication in patients receiving cytotoxic therapy. Report ofa prospective study. Gastroenterology 1991;100:182–8.
[10] Soh LT, Ang PT, Sng I, Chua EJ, Ong YW. Fulminant hepatic fail-ure in non-Hodgkin lymphoma patients treated with chemotherapy.European Journal of Cancer 1992;28:1338–9.
[11] Yeo W, Chan PK, Hui P, et al. Hepatitis B virus reactivation in
breast cancer patients receiving cytotoxic chemotherapy: a prospec-tive study. Journal of Medical Virology 2003;70:553–61.
[12] 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 Onc
M. Mandalà et al. / Critical Reviews
in patients positive for HBV surface antigen undergoing autologoushematopoietic cell transplantation. Blood 2002;99:2324–30.
[13] Francisci D, Falcinelli F, Schiaroli E, et al. Reactivation of hepatitisB virus replication due to cytotoxic therapy: a five-year prospectivestudy. Tumori 2012;98:220–4.
[14] Nakamura Y, Motokura T, Fujita A, Yamashita T, Ogata E. Severehepatitis related to chemotherapy in hepatitis B virus carriers withhematologic malignancies. Survey in Japan, 1987–1991. Cancer1996;78:2210–5.
[15] Kohrt HE, Ouyang DL, Keeffe EB. Systematic review: lamivu-dine prophylaxis for chemotherapy-induced reactivation of chronichepatitis B virus infection. Alimentary Pharmacology and Therapeu-tics 2006;24:1003–16.
[16] Ries LA, Melbert D, Krapcho M, et al. SEER Cancer StatisticsReview, 1975–2003. Bethesda, MD: National Cancer Institute; 2005.
[17] Alter MJ. Epidemiology of hepatitis B in Europe and worldwide.Journal of Hepatology 2003;39:64–9.
[18] Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plusrituximab compared with CHOP alone in elderly patients with dif-fuse large-B-cell lymphoma. New England Journal of Medicine2002;346:235–42.
[19] Feugier P, Van Hoof A, Sebban C, et al. Long- term results ofthe R-CHOP study in the treatment of elderly patients with dif-fuse large B-cell lymphoma: a study by the Groupe d’Etude desLymphomes de l’Adulte. Journal of Clinical Oncology 2005;23:4117–26.
[20] Pfreundschuh M, Trümper L, Osterborg A, et al. CHOP-likechemotherapy plus rituximab versus CHOP-like chemotherapy alonein young patients with good-prognosis diffuse large-B-cell lym-phoma: a randomised controlled trial by the MabThera InternationalTrial (MInT) Group. Lancet Oncology 2006;7:379–91.
[21] Yeo W, Chan TC, Leung NWY, et al. Hepatitis B virus reactivationin lymphoma patients with prior resolved hepatitis B undergoinganticancer therapy with or without rituximab. Journal of ClinicalOncology 2009;27:605–11.
[22] Van der Kolk LE, Baars JW, Prins MH, van Oers MH. Rituximab treat-ment results in impaired secondary humoral immune responsiveness.Blood 2002;100:2257–9.
[23] Osterborg A, Dyer MJ, Bunjes D, et al. Phase II multicenter studyof human CD52 antibody in previously treated chronic lympho-cytic leukemia: European Study Group of CAMPATH-1H treatmentin chronic lymphocytic leukemia. Journal of Clinical Oncology1997;15:1567–74.
[24] Lazdina U, Alheim M, Nyström J, et al. Priming of cytotoxic Tcell responses to exogenous hepatitis B virus core antigen is B celldependent. Journal of General Virology 2003;84:139–46.
[25] Aksoy S, Harputluoglu H, Kilickap S, et al. Rituximab-relatedviral infections in lymphoma patients. Leukemia and Lymphoma2007;48:1307–12.
[26] Stasi R, Del Poeta G, Stipa E, et al. Response to B-cell depletingtherapy with rituximab reverts the abnormalities of T-cell sub-sets in patients with idiopathic thrombocytopenic purpura. Blood2007;110:2924–30.
[27] Tsutsumi Y, Tanaka J, Kawamura T, et al. Possible efficacy oflamivudine treatment to prevent hepatitis B virus reactivation due torituximab therapy in a patient with non-Hodgkin’s lymphoma. Annalsof Hematology 2004;83:58–60.
[28] Tur-Kaspa R, Shaul Y, Moore DD, et al. The glucocorticoid recep-tor recognizes a specific nucleotide sequence in hepatitis B virusDNA causing increased activity of the HBV enhancer. Virology1988;167:630–3.
[29] Matsue K, Kimura S, Takanashi Y, et al. Reactivation of hepatitisB virus after rituximab containing treatment in patients with CD20-
positive B-cell lymphoma. Cancer 2010;116:4769–76.
[30] Cheng AL, Hsiung CA, Su IJ, et al. Hepatitis B virus reactivationin lymphoma steroid-free chemotherapy decreases risk of hepatitis B
ology/Hematology 87 (2013) 12–27 25
virus (HBV) reactivation in HBV-carriers with lymphoma. Hepatol-ogy 2003;37:1320–8.
[31] Kim MK, Ahn JH, Kim SB, et al. Hepatitis B reactivation duringadjuvant anthracycline-based chemotherapy in patients with breastcancer: a single institution’s experience. Korean Journal of InternalMedicine 2007;22:237–43.
[32] Zhong S, Yeo W, Schroder C, et al. High hepatitis B virus (HBV)DNA viral load is an important risk factor for HBV reactivation inbreast cancer patients undergoing cytotoxic chemotherapy. Journal ofViral Hepatitis 2004;11:55–9.
[33] Alexopoulos CG, Vaslamatzis M, Hatzidimitriou G. Prevalence ofhepatitis B virus marker positivity and evolution of hepatitis B virusprofile, during chemotherapy, in patients with solid tumours. BritishJournal of Cancer 1999;81:69–74.
[34] Yeo W, Chan PKS, Zhong S, et al. Frequency of hepatitis B virusreactivation in cancer patients undergoing cytotoxic chemotherapy: aprospective study of 626 patients with identification of risk factors.Journal of Medical Virology 2000;62:299–307.
[35] Jang JW, Choi JY, Bae SH, et al. A randomized controlled studyof preemptive lamivudine in patients receiving transarterial chemo-lipiodolization. Hepatology 2006;43:233–40.
[36] Kusumoto S, Tanaka Y, Ueda R, Mizokami M. Reactivationof hepatitis B virus following rituximab-plus-steroid combinationchemotherapy. Journal of Gastroenterology 2011;46:9–16.
[37] Lau GK, Yiu HH, Fong DY, et al. Early is superior to deferredpreemptive lamivudine therapy for hepatitis B patients undergoingchemotherapy. Gastroenterology 2003;125:1742–9.
[38] Pei SN, Chen CH, Lee CM, et al. Reactivation of hepatitis B virusfollowing rituximab-based regimens: a serious complication in bothHBsAg-positive and HBsAg-negative patients. Annals of Hemato-logy 2009;89:255–62.
[39] Hui CK, Cheung WW, Zhang HY, Au WY, Yueng YH, LeungAY. Kinetics and risk of de novo hepatitis B infection inHBsAg-negative patients undergoing cytotoxic chemotherapy. Gas-troenterology 2006;131:59–68.
[40] Pérez-Alvarez R, Díaz-Lagares C, García-Hernández F, et al. BIO-GEAS Study Group. Hepatitis B virus (HBV) reactivation in patientsreceiving tumor necrosis factor (TNF)-targeted therapy: analysis of257 cases. Medicine 2011;90:359–71.
[41] Moses SE, Lim ZY, Sudhanva M, et al. Lamivudine prophylaxis andtreatment of hepatitis B virus-exposed recipients receiving reducedintensity conditioning hematopoietic stem cell transplants with alem-tuzumab. Journal of Medical Virology 2006;78:1560–3.
[42] Esteve M, Saro C, González-Huix F, et al. Chronic hepatitis Breactivation following infliximab therapy in Crohn’s disease patients:need for primary prophylaxis. Gut 2004;53:1363–5.
[43] Kumagai K, Takagi T, Nakamura S, et al. Hepatitis B virus carriersin the treatment of malignant lymphoma: an epidemiological study inJapan. Annals of Oncology 1997;8:107–9.
[44] Hoofnagle JH, Dusheiko GM, Schafer DF, et al. Reactivation ofchronic hepatitis B virus infection by cancer chemotherapy. Annalsof Internal Medicine 1982;96:447–9.
[45] Hui CK, Lie A, Au WY, et al. A long-term follow-up study on hepatitisB surface antigen-positive patients undergoing allogeneic hematopoi-etic stem cell transplantation. Blood 2005;106:464–9.
[46] Pungpapong S, Kim WR, Poterucha JJ. Natural history of hepatitisB virus infection: an update for clinicians. Mayo Clinic Proceedings2007;82:967–75.
[47] Fukushima N, Mizuta T, Tanaka M, et al. Retrospective andprospective studies of hepatitis B virus reactivation in malignantlymphoma with occult HBV carrier. Annals of Oncology 2009;20:2013–7.
[48] Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hepatitis B
virus infection. Journal of Hepatology 2007;46:160–70.
[49] Urbani S, Fagnoni F, Missale G, Franchini M. The role of anti-core antibody response in the detection of occult hepatitis B virus
2 in Onc
6 M. Mandalà et al. / Critical Reviews
infection. Clinical Chemistry and Laboratory Medicine 2010;48:23–9.
[50] Siagris D, Christofidou M, Triga K, et al. Occult hepatitis B virusinfection in hemodialysis patients with chronic HCV infection. Jour-nal of Nephrology 2006;19:327–33.
[51] Kanbay M, Gur G, Akcay A, et al. Is hepatitis C virus positivity acontributing factor to occult hepatitis B virus infection in hemodialysispatients? Digestive Diseases and Sciences 2006;51:1962–6.
[52] Sayan M, Dogan C. Genotype/subgenotype distribution of hepatitis Bvirus among hemodialysis patients with chronical hepatitis B. Annalsof Hepatology 2012;11:849–54.
[53] Nunez M, Rios P, Perez-Olmeda M, Soriano V. Lack of‘occult’ hepatitis B virus infection in HIV-infected patients. AIDS2002;16:2099–101.
[54] Minuk GY, Sun DF, Uhanova J, et al. Occult hepatitis B virus infec-tion in a North American community-based population. Journal ofHepatology 2005;42:480–5.
[55] Kim SM, Lee KS, Park CJ, et al. Prevalence of occult HBV infectionamong subjects with normal serum ALT levels in Korea. Journal ofInfection 2007;54:185–91.
[56] Hui CK, Sun J, Au WY, et al. Occult hepatitis B virus infection inhematopoietic stem cell donors in a hepatitis B virus endemic area.Journal of Hepatology 2005;42:813–9.
[57] Koo YX, Tay M, Teh YE, et al. Risk of hepatitis B virus (HBV)reactivation in hepatitis B surface antigen negative/hepatitis B coreantibody positive patients receiving rituximab-containing combina-tion chemotherapy without routine antiviral prophylaxis. Annals ofHematology 2011;90:1219–23.
[58] Viganò M, Vener C, Lampertico P, et al. Risk of hepatitis B sur-face antigen seroreversion after allogeneic hematopoietic SCT. BoneMarrow Transplantation 2011;46:125–31.
[59] Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA. Hepatitis B virusDNA contains a glucocorticoid-responsive element. Proceedings ofthe National Academy of Sciences of the United States of America1986;83:1627–31.
[60] Weinbaum CM, Williams I, Mast EE, et al. Centers for Disease Con-trol and Prevention. Recommendations for identification and publichealth management of persons with chronic hepatitis B virus infection.MMWR: Recommendations and Reports 2008;57:1–20.
[62] Artz AS, Somerfield MR, Feld JJ, et al. American Society of Clini-cal Oncology provisional clinical opinion: chronic hepatitis B virusinfection screening in patients receiving cytotoxic chemotherapyfor treatment of malignant diseases. Journal of Clinical Oncology2010;28:3199–202.
[63] Barclay S, Pol S, Mutimer D, et al. The management of chronic hep-atitis B in the immunocompromised patient: recommendations froma single topic meeting. Journal of Clinical Virology 2008;42:104–15.
[64] European Association for the Study of the Liver. EASL ClinicalPractice Guidelines: management of chronic hepatitis B. Journal ofHepatology 2009;50:227–42.
[65] Niitsu N, Hagiwara Y, Tanae K, Kohri M, Takahashi N. Prospectiveanalysis of hepatitis B virus reactivation in patients with diffuse largeB-cell lymphoma after rituximab combination chemotherapy. Journalof Clinical Oncology 2010;28:5097–100.
[66] Tran TT, Rakoski MO, Martin P, Poordad F. Screening for hep-atitis B in chemotherapy patients: survey of current oncologypractices. Alimentary Pharmacology and Therapeutics 2010;31:240–6.
[67] Day FL, Karnon J, Rischin D. Cost-effectiveness of universal hep-atitis B virus screening in patients beginning chemotherapy for solidtumors. Journal of Clinical Oncology 2011;29:3270–7.
[68] Zurawska U, Hicks LK, Woo G, et al. Hepatitis B virus screeningbefore chemotherapy for lymphoma: a cost-effectiveness analysis.Journal of Clinical Oncology 2012;30:3167–73.
ology/Hematology 87 (2013) 12–27
[69] Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect ofpreventive lamivudine on hepatitis B reactivation during chemother-apy. Annals of Internal Medicine 2008;148:519–28.
[70] Chang TT, Gish RG, de Man R, et al. A comparison of entecavir andlamivudine for HBeAg-positive chronic hepatitis B. New EnglandJournal of Medicine 2006;354:1001–10.
[71] Perez-Roldan F, Gonzalez-Carro P, Villafanez-Garcia MC. Adefovirdipivoxil for chemotherapy-induced activation of hepatitis B virusinfection. New England Journal of Medicine 2005;352:310–1.
[72] Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine forpatients with HBeAg-negative chronic hepatitis B. New England Jour-nal of Medicine 2006;354:1011–20.
[73] Zhao SS, Tang L, Fan X, Chen L, Zhou R, Dai X. Comparison ofthe efficacy of lamivudine and telbivudine in the treatment of chronichepatitis B: a systematic review. Virology Journal 2010;7:11–8.
[74] Zhao SS, Tang LH, Dai XH, et al. Comparison of the efficacy of teno-fovir and adefovir in the treatment of chronic hepatitis B: a systematicreview. Virology Journal 2011;8:111–8.
[75] Dai MS, Chao TY. Lamivudine therapy in HBsAg-carrying breast can-cer patients undergoing chemotherapy: prophylactic or preemptive?Breast Cancer Research and Treatment 2005;92:95–6.
[76] Yeo W, Ho WM, Hui P, et al. Use of lamivudine to preventhepatitis B virus reactivation during chemotherapy in breast can-cer patients. Breast Cancer Research and Treatment 2004;88:209–15.
[77] Long M, Jia W, Li S, et al. A single-center, prospective and random-ized controlled study: can the prophylactic use of lamivudine preventhepatitis B virus reactivation in hepatitis B s-antigen seropositivebreast cancer patients during chemotherapy? Breast Cancer Researchand Treatment 2011;127:705–12.
[78] Loomba R, Liang TJ. Novel approaches to new therapies for hepatitisB virus infection. Antiviral Therapy 2006;11:1–15.
[79] Hui CK, Lie A, Au WY, et al. Effectiveness of prophylactic Anti-HBV therapy in allogeneic hematopoietic stem cell transplantationwith HBsAg positive donors. American Journal of Transplantation2005;5:1437–45.
[80] Giaccone L, Festuccia M, Marengo A, et al. Hepatitis B virusreactivation and efficacy of prophylaxis with lamivudine in patientsundergoing allogeneic stem cell transplantation. Biology of Bloodand Marrow Transplantation 2010;16:809–17.
[81] Ceneli O, Ozkurt ZN, Acar K, et al. Hepatitis B-related events inautologous hematopoietic stem cell transplantation recipients. WorldJournal of Gastroenterology 2010;16:1765–71.
[82] Borentain P, Colson P, Coso D, et al. Clinical and virological fac-tors associated with hepatitis B virus reactivation in HBsAg-negativeand anti-HBc antibodies-positive patients undergoing chemotherapyand/or autologous stem cell transplantation for cancer. Journal of ViralHepatitis 2010;17:807–15.
[83] Hammond SP, Borchelt AM, Ukomadu C, Ho VT, Baden LR, MartyFM. Hepatitis B virus reactivation following allogeneic hematopoieticstem cell transplantation. Biology of Blood and Marrow Transplan-tation 2009;15:1049–59.
[84] Ji D, Cao J, Hong X, et al. Low incidence of hepatitis Bvirus reactivation during chemotherapy among diffuse large B-cell lymphoma patients who are HBsAg-negative/HBcAb-positive:a multicenter retrospective study. European Journal of Haematology2010;85:243–50.
[85] Weinbaum CM, Williams I, Mast EE, et al. Centers for Disease Con-trol and Prevention. Recommendations for identification and publichealth management of persons with chronic hepatitis B virus infection.MMWR: Recommendations and Reports 2008;57(RR-8):1–20.
[86] Sorrell MF, Belongia EA, Costa J, et al. National Institutes of Healthconsensus development conference statement: management of hep-
atitis B. Hepatology 2009;49(5 Suppl.):S4–12.
[87] APASL Guidelines for HBV Management. Hepatology International2008;2:263–83.
in Onc
B
UaRviwOi2cscSmicof Thrombosis and Haemostasis, Thrombosis and Hemosta-sis, Arteriosclerosis – Thrombosis and Vascular Biology,Critical Review in Oncology and Hematology.
M. Mandalà et al. / Critical Reviews
[88] Morotta P, Lucas K. Management of hepatitis B: a longi-tudinal national survey – impact of the Canadian HepatitisB Consensus Guidelines. Canadian Journal of Gastroenterology2010;24(9):537–42.
[89] Yeo W, Hui EP, Chan AT, et al. Prevention of hepatitis B virusreactivation in patients with nasopharyngeal carcinoma with lamivu-dine. American Journal of Clinical Oncology 2005;28:379–84.
[90] Dai MS, Wu PF, Shyu RY, Lu JJ, Chao TY. Hepatitis B virusreactivation in breast cancer patients undergoing cytotoxic chemother-apy and the role of preemptive lamivudine administration. LiverInternational 2004;24:540–6.
[91] Dai MS, Wu PF, Lu JJ, Shyu RY, Chao TY. Preemptive use of lamivu-dine in breast cancer patients carrying hepatitis B virus undergoingcytotoxic chemotherapy: a longitudinal study. Supportive Care inCancer 2004;12:191–6.
[92] Yun J, Kim KH, Kang ES, et al. Prophylactic use of lamivudinefor hepatitis B exacerbation in post-operative breast cancer patientsreceiving anthracycline-based adjuvant chemotherapy. British Journalof Cancer 2011;104:559–63.
[93] Sohn BS, Ahn JH, Jung KH, et al. Updated longitudinal data on acuteexacerbation of chronic hepatitis B in patients with breast cancerreceiving anthracycline-based adjuvant chemotherapy: therapeutic vs.pre-emptive use of lamivudine. Japanese Journal of Clinical Oncology2011;41:59–66.
[94] Nagamatsu H, Itano S, Nagaoka S, et al. Prophylactic lamivu-dine administration prevents exacerbation of liver damage in HBeantigen positive patients with hepatocellular carcinoma undergoingtranshepatic arterial infusion chemotherapy. American Journal ofGastroenterology 2004;99:2369–75.
[95] Hsu C, Hsiung CA, Su IJ, et al. A revisit of prophylactic lamivudine forchemotherapy-associated hepatitis B reactivation in non-Hodgkin’slymphoma: a randomized trial. Hepatology 2008;47:844–53.
[96] Idilman R, Arat M, Soydan E, et al. Lamivudine prophylaxis for pre-vention of chemotherapy-induced hepatitis B virus reactivation inhepatitis B virus carriers with malignancies. Journal of Viral Hepatitis2004;11:141–7.
[97] Shibolet O, Ilan Y, Gillis S, Hubert A, Shouval D, Safadi R. Lamivu-dine therapy for prevention of immunosuppressive-induced hepatitisB virus reactivation in hepatitis B surface antigen carriers. Blood2002;100:391–6.
[98] Leaw SJ, Yen CJ, Huang WT, Chen TY, Su WC, Tsao CJ. Preemp-tive use of interferon or lamivudine for hepatitis B reactivation inpatients with aggressive lymphoma receiving chemotherapy. Annalsof Hematology 2004;83:270–5.
[99] Lee GW, Ryu MH, Lee JL, et al. The prophylactic use of lamivudinecan maintain dose-intensity of adriamycin in hepatitis-B surface anti-gen (HBs Ag)-positive patients with non-Hodgkin’s lymphoma whoreceive cytotoxic chemotherapy. Journal of Korean Medical Science2003;18:849–54.
[100] Li YH, He YF, Jiang WQ, et al. Lamivudine prophylaxis reducesthe incidence and severity of hepatitis in hepatitis B virus carri-ers who receive chemotherapy for lymphoma. Cancer 2006;106:1320–5.
ology/Hematology 87 (2013) 12–27 27
[101] Persico M, De Marino F, Russo GD, et al. Efficacy of lamivu-dine to prevent hepatitis reactivation in hepatitis B virus-infectedpatients treated for non-Hodgkin lymphoma. Blood 2002;99:724–5.
[102] Chen XQ, Peng JW, Lin GN, Li M, Xia ZJ. The effectof prophylactic lamivudine on hepatitis B virus reactivation inHBsAg-positive patients with diffuse large B-cell lymphoma under-going prolonged rituximab therapy. Medical Oncology 2012;29:1237–41.
[103] Li HR, Huang JJ, Guo HQ, Li M, Xia ZJ. Comparison of ente-cavir and lamivudine in preventing hepatitis B reactivation inlymphoma patients during chemotherapy. Journal of Viral Hepatitis2011;18:877–83.
[104] Tsutsumi Y, Shigematsu A, Hashino S, et al. Analysis of reactivationof hepatitis B virus in the treatment of B cell non-Hodgkin’s lym-phoma in Hokkaido. Annals of Hematology 2009;88:375–7.
[105] Kim JS, Hahn JS, Park SY, et al. Long-term outcome after pro-phylactic lamivudine treatment on hepatitis B virus reactivationin non-Hodgkin’s lymphoma. Yonsei Medical Journal 2007;48:78–89.
iography
Mario Mandalà is currently a Medical Oncologist in thenit of Medical Oncology, Riuniti Bergamo Hospital in Berg-
mo, Italy. He is in charge of the Clinical and Traslationalesearch Unit. He received his M.D. from the Catholic Uni-ersity in Rome, Italy in 1995. He has completed residenciesn Medical Oncology at the Catholic University in Rome asell as at Milan University and the European Institute ofncology in Milan, Italy. He also obtained diplomas in Med-
cal Oncology and Haematology from Milan University in000 and 2005, respectively. His research interests includelinical and translational research on cancer and thrombo-is. His main oncological research focuses on gastrointestinalancer and melanoma. He is a full member of the Europeanociety of Medical Oncology. He has lead- or co-authoredany scientific papers and is a reviewer for several journals,
ncluding Lancet Oncology, Cancer, British Journal of Can-er, Annals of Oncology, Cancer Treatment Review, Journal
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