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Hepatitis B, Rituximab, Screening, and Prophylaxis:Effectiveness and Cost EffectivenessAnnette E. Hay and Ralph M. Meyer, NCIC Clinical Trials Group; Queens University, Kingston, Ontario, Canada

See accompanying article on page 3167

An important role of medical journals is to communicate infor-

mation between stakeholder groups.1,2 These communications may

be between researchers about findings that inform future research;

results of phase I-II trials inJournal of Clinical Oncology (JCO)exem-

plifythispurpose.Alternately,communicationsbetween practitionerscan advise about implementing clinical practices, such as with narra-

tive reviews and case-based manuscripts including JCOsOncology

Grand Rounds, which provide guidance to practitioners.3 Communi-

cations from investigators to practitioners and policy makers include

resultsof randomizedcontrolled trials(RCTs)andsystematicreviews.

Thesecommunicationsinform decisionsaboutmanaging individualpa-

tients and health care delivery policies. For policy determination, eco-

nomicevaluations also have an importantrole. Implicit inconducting an

economicanalysisispriordemonstrationthattheintervention iseffective.

With this knowledge in hand, understanding economic ramifications of

adopting an intervention may be very helpful: a central premise is that

resourcesarescarceanddecisionsaboutalternativesareassociatedwithan

opportunity cost because resourcesused foronepurpose are unavailablefor another use.JCOhas provided guidance to researchers intending to

submita reportof aneconomicanalysis4; high priorityisgiventoanalyses

that affectdecisionsabout adoption.

In the article that accompanies this editorial, Zurawska et al5

provide a cost-effectiveness analysis assessing hepatitis B virus (HBV)

screeningbefore administeringrituximab,cyclophosphamide,doxoru-

bicin, vincristine and prednisone (R-CHOP) chemotherapy to patients

with diffuse large B-cell lymphoma (DLBCL). Their analysis links data

demonstrating that when treated withR-CHOP, patients with DLBCL

who are chronically infected with HBV can experience reactivation of

HBV infection leading to acute hepatitis with consequences including

morbidityassociatedwithinfection,compromiseof chemotherapy deliv-

erythat might resultin morbidityandmortalityassociated with subopti-

mal control of lymphoma, and death from fulminant hepatitis.6,7 This

analysis assumes that effective strategies for screening and prophylaxis

exist. The authors conclude that routine screening of all patients with

DLBCL before chemotherapy is cost effective because, in comparison

with alternatives, it is least costly and associated with superior 1-year

survival. Setting aside the above assumptions and implications of the

authorsconclusions, thisanalysisfollowspublishedrulesfor reportingan

economic evaluation,8 as the study question includes clear alternatives

(screen all, screen high-risk patients, screen none), the perspective of the

analysis is provided (a Canadian provinces Ministry of HealthandLong

Term Care), costing appears to be comprehensive and credibly valued,

andresults were provided using incremental differences and with associ-

ated sensitivity analyses. A minor criticism is that conclusions may be

overstated because the differences in costs and life-years saved between

alternativesaremarginal;stating that a screen-all strategy falls well within

standard benchmarks for cost effectiveness would be a more conserva-tively stated conclusion. Screening all patients with DLBCL would be

expected to be even more cost effective in jurisdictions with HBV preva-

lence rates that exceedthose observed in Canada.

At issue is howthiseconomic analysisinforms decisions to adopt

a strategyto screenallpatients with DLBCL for HBV. Otherinforma-

tion helps to frameZurawska et als5 conclusions.First, the problemis

important:reactivationofHBVinpatientswithcancerreceivingchem-

otherapy is recognized and available data show that this risk is increased

withthemoreprofoundimmunosuppressionassociatedwith lymphoma

and treatment that includes steroids and now rituximab.6,7,9 Second,

authors of a meta-analysis7 that includedtwoRCTsandadditional obser-

vational data concludedthat whilethesedata are associated withimpor-

tant limitations, a reasonable interpretation is that prophylaxis withlamivudine is preferred over a no-treatment approach when patients

withcancertestingpositiveforhepatitis B surfaceantigen(HBsAg)are

treated with chemotherapy. Third, synthesis of these two points has

resultedinpublication of numerousguidelinesrecommending screening

for HBV and antiviral prophylaxis for cancer patients with positive

testing10-15 (Table 1), especially when rituximab is used to treat lym-

phoma. Screening has also been recommended for patients who

are to receive rituximab for treatment of benign conditions.16

Finally, despite these guidelines, practice variation exists with

poor uptake of these recommendations: Zurawska et al cite data

reporting routine screening in their geographic region of only

14% of patients with cancer who are to receive chemotherapy,17

an Australian survey that included oncologists who treat lym-

phoma reported that 47% never screen for HBV before initiat-

ing chemotherapy18 and in a North American teaching hospital

only 36.6% of patients treated with rituximab between 1997 and

2009 had HBV testing although rates increased to 67.4% after

introduction of guidelines.19

A previous survey has suggested that one reason for variable

adoption may be concern about cost effectiveness.18 Zurawska et als5

conclusions might thus promote adoption of screening for patients

with lymphoma, especially if concerns about cost effectiveness were

accentuated by a recent publication in JCOby Day et al,20 which

deemed routine prechemotherapy screening of patients with solid

JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L

V O L UM E 3 0 N U MB E R 2 6 S E P TE M B ER 1 0 2 0 1 2

2012 by American Society of Clinical Oncology 3155Journal of Clinical Oncology, Vol 30, No 26 (September 10), 2012: pp 3155-3157

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tumors cost ineffective. In that analysis, the cost per life-year saved was

$88,224 for patients receiving adjuvant therapy and $1,344,251 for pa-tients receiving palliative chemotherapy (values in Australian dollars).

ReviewofthemethodologiesoftheDayetalandZurawskaetaleconomic

evaluations prompt speculation that botheffectivenessand costeffective-ness of screeningand prophylaxisareamplifiedforpatientswith DLBCL.

In comparison with populations of other patients with cancer receiving

chemotherapy, those with DLBCL mayhave greater background risks ofHBV infection, experience more severe immunosuppression, and are

treated with curative rather than palliative intent and in a manner that is

associated with effect sizes that exceed those anticipated when treatingmost patients with solid tumors. These differences are now even greater

because,incomparisonwith CHOP,R-CHOP isassociatedwithsuperiordisease control andoverall survival,butalso is more immunosuppressive

and appears to be associated with greater risks of HBV reactivation, and

clinical and severe HBV-related hepatitis.21 Thus, preventing HBV reac-tivation is now more important and success should be associated with

opportunities for greater benefit. These suppositions also support an ar-

gument that the 1-year survival end point used by Zurawska et al isconservative, as long-term survival and the morbidity associated

with HBV reactivation are undervalued.

Will Zurawska et als5 analysis alter physician behaviors, strengthenrecommendations from professional societies and health care agencies,

andreducepracticevariation?Whileacommonlyrecommendedpractice

policy is now associated with favorable economic parameters, a largerquestion relates to a core principle of economic evaluations and the as-

sumptions onwhich this analysiswasbased: is there sufficient evidence

demonstrating effectiveness of screening and prophylaxis strategiesforHBV?In 2010, theAmerican Societyof Clinical Oncology (ASCO)

provided a Provisional Clinical Opinion12 (PCO) addressing these

questions (Table 1); the PCO included different conclusions thanthose recommendedby other agencies andthe reasonfor these differ-

ences may help explain why incomplete adoption has occurred. In

contrast with other bodies, such as the U.S. Center for Disease Con-trol,10 the ASCO PCO concluded insufficient evidence exists to deter-

mine net benefits andharms for routine screening in individuals with

cancerand recommends screening only be considered (as opposed touniversallyperformed)forpatientswith lymphoma whoaretoreceive

rituximab; the conclusion that there was inadequate evidenceapplied

to both HBsAg testing as a screening tool and to prophylactic treat-ment for those with a positive test. The conceptual basis of the PCO

process includes recognition that new scientific evidence is complex,

developsrapidly andthat thelabel ofProvisional necessitatesregularreview in order to assure that a goal to answer does this change my

practice? is addressed.22 So, at least with respect to treating DLBCL,

should the ASCO PCO be updated? If updated, Zurawska et alsanalysis indicates that effectiveness of prophylaxis should be empha-

sized; while not minimizing the importance of what constitutes opti-

mum screening, their data suggest that even for populations withrelatively low prevalence rates, screening is likely to be cost effective.

The ASCO PCO statements couldbe considered forthree popu-lations: patients with nonlymphoma cancer, patients with DLBCL

who were previously treated with CHOP and current patients with

DLBCL undergoing active treatment withR-CHOP. Policies forthosewith solid tumors require separate consideration as these patients are

less likely to develop severe hepatitis, and patients receiving palliative

chemotherapy for metastatic disease are more likely to have cancer-related risks that affect morbidity and mortality. The uncertainties

associated with limited evidence referred to in the ASCO PCO most

directly apply to this population. Zurawska et als5 analysis requiresthat up-to-date lymphoma-specific evidence be considered. The only

two RCTs evaluating patients with DLBCL23,24 included treatment

with CHOP, and notR-CHOP, and contributed to the assumptionsused by Zurawska et al. Results of these trials showed reduced rates of

HBV reactivation and HBV-related clinical hepatitis and severe hep-

atitis. The magnitude of reduction of clinically apparent HBV hepatitis(45%versus 5%) was substantial, but the pooledsamplesize was only 84

patients. These trialsprovide insufficient data forconclusions about risks

of clinical hepatitisfollowing cessation of prophylactic therapy andlong-term survival, but were interpreted by developers of most guidelines as

Table 1. Selected Guidance Documents With Recommendations for Hepatitis B Screening

Recommending BodyPatient Groups Included/Recommendation

for Screening Serological Tests Prophylaxis

Centers for Disease Control10 Patients receiving cytotoxic or immunosuppressivetherapy/Screen all

HBsAg, anti-HBc, anti-HBs Prophylactic antiviral therapy for HBsAg-positive patients

American Association for theStudy of LiverDiseases11

Patients receiving cytotoxic or immunosuppressivetherapy/Screen all high-risk patients

HBsAg, anti-HBc Lamivudine, telbivudine, tenofovir orentecavir for all HBV carriers. Continuefor 6 mo post oncologic therapy

American Society of ClinicalOncology12

Patients receiving cytotoxic or immunosuppressivetherapy/Consider screening high-risk groupsand those receiving highly immunosuppressivetherapy

HBsAg, anti-HBc in somepopulations

Consider antiviral therapy with evidence ofchronic HBV infection

European Society for MedicalOncology13

Follicular lymphoma/Screen all Not specified Prophylactic antiviral therapy for HBsAg-positive patients

British Committee forStandardsin Haematology14

Follicular lymphoma/Screen all at baseline andre-screen high-risk patients pre- immunotherapy

Not specified Not specified

National ComprehensiveCancer Network15

Non-Hodgkins lymphoma/Screen all receivingrituximab, from areas with high or unknownHBV prevalence and receiving chemotherapy

HBsAg, anti-HBc. Add e-antigenif risk factors or history ofHBV

Prophylactic antiviral therapy for patientswith a positive test. Monitor viral loadwith PCR monthly. Lamivudine is notthe optimal prophylactic agent

Rituximab Consensus ExpertCommittee16

Rheumatoid arthritis/Screen all receiving rituximab HBsAg, anti-HBc Prophylactic antiviral therapy for HBsAg oranti HBc-positive patients

Abbreviations: anti-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitisB virus; PCR, polymerase chain reaction.

Editorial

3156 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY



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sufficientforadoption of prophylaxis.UseofR-CHOPcreates newcom-plexities. Risks of reactivation in patients with HBsAg positivity are in-

creasedanda newriskgroupisrecognized that includesthosewith testing

that is negative for HBsAg but positive for hepatitis B core antibody(anti-HBc).9,21 Furthermore, R-CHOP is associated with reactivation

risksthat persist aftercompletingprophylactic therapy,25,26 a finding that

coincides with discovery of the YMDD mutation,27 which is associatedwithlamivudineresistance.Thus,guidelineshavemovedbeyondwhether

thesepatientsshouldbescreenedandreceiveprophylaxisandontodebate

about which screening tests to employ, which prophylactic agent to useand theoptimum duration of therapy. These debates assumethat added

risks associated with rituximab-related HBV reactivation create a larger

population in need of prophylaxis and that the efficacy of prophylaxisobserved in two small RCTs evaluating patients treated with CHOP will

notbecompromisedbythemoresevereandprolongedimmunosuppres-

sion associatedwith R-CHOP.It is unlikely that practitioners and policy makers will be in-

formedwithdefinitivedata fromRCTsinthenearfuture. Asindicated

by Zurawska et al,5 a RCT evaluatingscreening will probably never beperformed. Thus, communicationsto practitioners andpolicymakers

about todaysbestpracticesneedto emphasize theimportanceandyetremaininguncertaintiesassociated withthis decision-makingprocess.Theeconomic analysisof Zurawskaet al provides helpful information

addressing one of these uncertainties. Their workcontributesto avail-

able information supporting as a standard of care routine HBVscreening of patients with DLBCL who are to receive R-CHOP and

provision of prophylactic therapy to those with a positive test.

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although allauthors completed the disclosuredeclaration, thefollowing author(s)and/or an authorsimmediate family member(s) indicated a financialor otherinterestthatis relevant to the subject matter under consideration in this article.Certain relationships markedwitha Uare those for which no compensation wasreceived; those relationships marked with a C werecompensated. Fora detailed

descriptionof the disclosure categories, or formoreinformation about ASCOsconflict of interestpolicy,please refer to the Author Disclosure Declarationand theDisclosuresof Potential Conflicts of Interestsectionin InformationforContributors.Employment or Leadership Position: None Consultant or AdvisoryRole:NoneStock Ownership:NoneHonoraria:Ralph M. Meyer, EliLilly, CelgeneResearch Funding:Ralph M. Meyer, Amgen, ARIADPharmaceuticals, Astex Therapeutics, AstraZeneca, Boston Biomedical,Bristol-Myers Squibb, Celgene, Geron, GalxoSmithKline, JanssenPharmaceuticals, Eli Lilly, Merck Frosst Canada, Novartis, OncolyticsBiotech, Oncothyreon, Pfizer, Roche, sanofi-aventis, Schering-PloughCanadaExpert Testimony:NoneOther Remuneration:None

AUTHOR CONTRIBUTIONS

Provision of study materials or patients: Annette E. HayManuscript writing:All authorsFinal approval of manuscript: All authors

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www.jco.org on August 13, 2012

Editorial

www.jco.org 2012 by American Society of Clinical Oncology 3157

http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Chronic_Hep_B_Update_2009%208_24_2009.pdfhttp://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Chronic_Hep_B_Update_2009%208_24_2009.pdfhttp://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Chronic_Hep_B_Update_2009%208_24_2009.pdfhttp://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Chronic_Hep_B_Update_2009%208_24_2009.pdfhttp://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Chronic_Hep_B_Update_2009%208_24_2009.pdfhttp://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Chronic_Hep_B_Update_2009%208_24_2009.pdf

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