VOLUME 30 NUMBER 26 SEPTEMBER 10 2012

JOURNAL OF CLINICAL ONCOLOGY

Hepatitis B, Rituximab, Screening, and Prophylaxis:

Effectiveness and Cost Effectiveness
Annette 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 information between stakeholder groups.1,2 These communications may
be between researchers about findings that inform future research;
results of phase I-II trials in Journal of Clinical Oncology (JCO) exemplify this purpose. Alternately, communications between practitioners
can advise about implementing clinical practices, such as with narrative reviews and case-based manuscripts including JCOs Oncology
Grand Rounds, which provide guidance to practitioners.3 Communications from investigators to practitioners and policy makers include
results of randomized controlled trials (RCTs) and systematic reviews.
These communications inform decisions about managing individual patients and health care delivery policies. For policy determination, economic evaluations also have an important role. Implicit in conducting an
economicanalysisispriordemonstrationthattheinterventioniseffective.
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 resources used for one purpose are unavailable
for another use. JCO has provided guidance to researchers intending to
submit a report of an economic analysis4; high priority is given to analyses
that affect decisions about adoption.
In the article that accompanies this editorial, Zurawska et al5
provide a cost-effectiveness analysis assessing hepatitis B virus (HBV)
screening before administering rituximab, cyclophosphamide,doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy to patients
with diffuse large B-cell lymphoma (DLBCL). Their analysis links data
demonstrating that when treated with R-CHOP, patients with DLBCL
who are chronically infected with HBV can experience reactivation of
HBV infection leading to acute hepatitis with consequences including
morbidity associated with infection, compromise of chemotherapy delivery that might result in morbidity and mortality associated with suboptimal 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
authors conclusions, this analysis follows published rules for reporting an
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 Health and Long
Term Care), costing appears to be comprehensive and credibly valued,
Journal of Clinical Oncology, Vol 30, No 26 (September 10), 2012: pp 3155-3157

and results were provided using incremental differences and with associated sensitivity analyses. A minor criticism is that conclusions may be
overstated because the differences in costs and life-years saved between
alternatives are marginal; stating that a screen-all strategy falls well within
standard benchmarks for cost effectiveness would be a more conservatively stated conclusion. Screening all patients with DLBCL would be
expected to be even more cost effective in jurisdictions with HBV prevalence rates that exceed those observed in Canada.
At issue is how this economic analysis informs decisions to adopt
a strategy to screen all patients with DLBCL for HBV. Other information helps to frame Zurawska et als5 conclusions. First, the problem is
important:reactivationofHBVinpatientswithcancerreceivingchemotherapy is recognized and available data show that this risk is increased
with the more profound immunosuppression associated with lymphoma
and treatment that includes steroids and now rituximab.6,7,9 Second,
authors of a meta-analysis7 that included two RCTs and additional observational data concluded that while these data are associated with important limitations, a reasonable interpretation is that prophylaxis with
lamivudine is preferred over a no-treatment approach when patients
with cancer testing positive for hepatitis B surface antigen (HBsAg) are
treated with chemotherapy. Third, synthesis of these two points has
resulted in publication of numerous guidelines recommending screening
for HBV and antiviral prophylaxis for cancer patients with positive
testing10-15 (Table 1), especially when rituximab is used to treat lymphoma. 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 lymphoma reported that 47% never screen for HBV before initiating 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 JCO by Day et al,20 which
deemed routine prechemotherapy screening of patients with solid
2012 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on December 22, 2014. For personal use only. No other uses without permission.
Copyright 2012 American Society of Clinical Oncology. All rights reserved.

3155

Editorial

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

Recommending Body

Patient Groups Included/Recommendation

for Screening

Centers for Disease Control10 Patients receiving cytotoxic or immunosuppressive

therapy/Screen all
American Association for the Patients receiving cytotoxic or immunosuppressive
therapy/Screen all high-risk patients
Study of Liver
Diseases11
American Society of Clinical Patients receiving cytotoxic or immunosuppressive
Oncology12
therapy/Consider screening high-risk groups
and those receiving highly immunosuppressive
therapy
European Society for Medical Follicular lymphoma/Screen all
13
Oncology
Follicular lymphoma/Screen all at baseline and
British Committee for
re-screen high-risk patients pre- immunotherapy
Standards
in Haematology14
Non-Hodgkins lymphoma/Screen all receiving
National Comprehensive
rituximab, from areas with high or unknown
Cancer Network15
HBV prevalence and receiving chemotherapy
Rituximab Consensus Expert
Committee16

Serological Tests
HBsAg, anti-HBc, anti-HBs
HBsAg, anti-HBc

HBsAg, anti-HBc in some

populations

Not specified
Not specified

Prophylaxis
Prophylactic antiviral therapy for HBsAgpositive patients
Lamivudine, telbivudine, tenofovir or
entecavir for all HBV carriers. Continue
for 6 mo post oncologic therapy
Consider antiviral therapy with evidence of
chronic HBV infection

Prophylactic antiviral therapy for HBsAgpositive patients

Not specified

HBsAg, anti-HBc. Add e-antigen Prophylactic antiviral therapy for patients

if risk factors or history of
with a positive test. Monitor viral load
HBV
with PCR monthly. Lamivudine is not
the optimal prophylactic agent
Rheumatoid arthritis/Screen all receiving rituximab HBsAg, anti-HBc
Prophylactic antiviral therapy for HBsAg or
anti 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, hepatitis
B virus; PCR, polymerase chain reaction.

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 patients receiving palliative chemotherapy (values in Australian dollars).
ReviewofthemethodologiesoftheDayetalandZurawskaetaleconomic
evaluations prompt speculation that both effectiveness and cost effectiveness of screening and prophylaxis are amplified for patients with DLBCL.
In comparison with populations of other patients with cancer receiving
chemotherapy, those with DLBCL may have greater background risks of
HBV 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 treating
most patients with solid tumors. These differences are now even greater
because, in comparison with CHOP, R-CHOP is associated with superior
disease control and overall survival, but also 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 reactivation is now more important and success should be associated with
opportunities for greater benefit. These suppositions also support an argument that the 1-year survival end point used by Zurawska et al is
conservative, as long-term survival and the morbidity associated
with HBV reactivation are undervalued.
Will Zurawska et als5 analysis alter physician behaviors, strengthen
recommendations from professional societies and health care agencies,
andreducepracticevariation?Whileacommonlyrecommendedpractice
policy is now associated with favorable economic parameters, a larger
question relates to a core principle of economic evaluations and the assumptions on which this analysis was based: is there sufficient evidence
demonstrating effectiveness of screening and prophylaxis strategies
for HBV? In 2010, the American Society of Clinical Oncology (ASCO)
provided a Provisional Clinical Opinion12 (PCO) addressing these
questions (Table 1); the PCO included different conclusions than
those recommended by other agencies and the reason for these differences may help explain why incomplete adoption has occurred. In
contrast with other bodies, such as the U.S. Center for Disease Control,10 the ASCO PCO concluded insufficient evidence exists to deter3156

2012 by American Society of Clinical Oncology

mine net benefits and harms for routine screening in individuals with
cancer and recommends screening only be considered (as opposed to
universally performed) for patients with lymphoma who are to receive
rituximab; the conclusion that there was inadequate evidence applied
to both HBsAg testing as a screening tool and to prophylactic treatment for those with a positive test. The conceptual basis of the PCO
process includes recognition that new scientific evidence is complex,
develops rapidly and that the label of Provisional necessitates regular
review 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 als
analysis indicates that effectiveness of prophylaxis should be emphasized; while not minimizing the importance of what constitutes optimum screening, their data suggest that even for populations with
relatively low prevalence rates, screening is likely to be cost effective.
The ASCO PCO statements could be considered for three populations: patients with nonlymphoma cancer, patients with DLBCL
who were previously treated with CHOP and current patients with
DLBCL undergoing active treatment with R-CHOP. Policies for those
with 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 cancerrelated 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 requires
that up-to-date lymphoma-specific evidence be considered. The only
two RCTs evaluating patients with DLBCL23,24 included treatment
with CHOP, and not R-CHOP, and contributed to the assumptions
used by Zurawska et al. Results of these trials showed reduced rates of
HBV reactivation and HBV-related clinical hepatitis and severe hepatitis. The magnitude of reduction of clinically apparent HBV hepatitis
(45% versus 5%) was substantial, but the pooled sample size was only 84
patients. These trials provide insufficient data for conclusions about risks
of clinical hepatitis following cessation of prophylactic therapy and longterm survival, but were interpreted by developers of most guidelines as
JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on December 22, 2014. For personal use only. No other uses without permission.
Copyright 2012 American Society of Clinical Oncology. All rights reserved.

Editorial

sufficient for adoption of prophylaxis. Use of R-CHOP creates new complexities. Risks of reactivation in patients with HBsAg positivity are increased and a new risk group is recognized that includes those with testing
that is negative for HBsAg but positive for hepatitis B core antibody
(anti-HBc).9,21 Furthermore, R-CHOP is associated with reactivation
risks that persist after completing prophylactic therapy,25,26 a finding that
coincides with discovery of the YMDD mutation,27 which is associated
withlamivudineresistance.Thus,guidelineshavemovedbeyondwhether
thesepatientsshouldbescreenedandreceiveprophylaxisandontodebate
about which screening tests to employ, which prophylactic agent to use
and the optimum duration of therapy. These debates assume that added
risks associated with rituximab-related HBV reactivation create a larger
population in need of prophylaxis and that the efficacy of prophylaxis
observed in two small RCTs evaluating patients treated with CHOP will
notbecompromisedbythemoresevereandprolongedimmunosuppression associated with R-CHOP.
It is unlikely that practitioners and policy makers will be informed with definitive data from RCTs in the near future. As indicated
by Zurawska et al,5 a RCT evaluating screening will probably never be
performed. Thus, communications to practitioners and policy makers
about todays best practices need to emphasize the importance and yet
remaining uncertainties associated with this decision-making process.
The economic analysis of Zurawska et al provides helpful information
addressing one of these uncertainties. Their work contributes to available information supporting as a standard of care routine HBV
screening 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 all authors completed the disclosure declaration, the following author(s)
and/or an authors immediate family member(s) indicated a financial or other
interest that is relevant to the subject matter under consideration in this article.
Certain relationships marked with a U are those for which no compensation was
received; those relationships marked with a C were compensated. For a detailed
description of the disclosure categories, or for more information about ASCOs
conflict of interest policy, please refer to the Author Disclosure Declaration and the
Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: None Stock Ownership: None Honoraria: Ralph M. Meyer, Eli
Lilly, Celgene Research Funding: Ralph M. Meyer, Amgen, ARIAD
Pharmaceuticals, Astex Therapeutics, AstraZeneca, Boston Biomedical,
Bristol-Myers Squibb, Celgene, Geron, GalxoSmithKline, Janssen
Pharmaceuticals, Eli Lilly, Merck Frosst Canada, Novartis, Oncolytics
Biotech, Oncothyreon, Pfizer, Roche, sanofi-aventis, Schering-Plough
Canada Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS

Provision of study materials or patients: Annette E. Hay

Manuscript writing: All authors
Final approval of manuscript: All authors
REFERENCES
1. Haynes RB: Loose Connections between peer-reviewed clinical journals
and clinical practice. Ann Intern Med 113:724-728, 1990
2. Meyer RM, Kouroukis CT: Understanding outcome measures. Evid Based
Oncol 2:172-176, 2001
3. Moran T, Sequist LV: Timing of epidermal growth factor receptor tyrosine
kinase inhibitor therapy in patients with lung cancer with EGFR mutations. J Clin
Oncol [epub ahead of print on July 2, 2012]
4. Levine MN, Ganz PA, Haller DG: Economic evaluation in the J Clin Oncol:
Past, present, and future. J Clin Oncol 25:614-616, 2007

5. Zarawska U, Hicks LK, Woo G, et al: Hepatitis B virus screening before

chemotherapy for lymphoma: A cost-effectiveness analysis. J Clin Oncol 30:
3167-3173, 2012
6. Liang R: How I treat and monitor viral hepatitis B infection in patients
receiving intensive immunosuppressive therapies or undergoing hematopoietic
stem cell transplantation. Blood 113:3147-3153, 2009
7. Loomba R, Rowley A, Wesley R, et al: Systematic review: The effect of
preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann
Intern Med 148:519-528, 2008
8. Department of Clinical Epidemiology and Biostatistics MUHSC: How to
read clinical journals: VII. To understand an economic evaluation (part B). Can
Med Assoc J 130:1542-1549, 1984
9. Yeo W, Chan TC, Leung NWY, et al: Hepatitis B virus reactivation in
lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy
with or without rituximab. J Clin Oncol 27:605-611, 2009
10. Weinbaum CM, Mast EE, Ward JW: Recommendations for identification
and public health management of persons with chronic hepatitis B virus infection.
Hepatology 49:S35-S44, 2009
11. Lok ASF, McMahon BJ: Chronic hepatitis B: Update 2009American Association for the Study of Liver Diseases: Practice guideline update. http://www.aasld.org/
practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/
Chronic_Hep_B_Update_2009%208_24_2009.pdf
12. Artz AS, Somerfield MR, Feld JJ, et al: American Society of Clinical
Oncology Provisional Clinical Opinion: Chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of malignant
diseases. J Clin Oncol 28:3199-3202, 2010
13. Dreyling M, Ghielmini M, Marcus R, et al: Newly diagnosed and relapsed
follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment
and follow-up. Ann Oncol 22:vi59-vi63, 2011 (suppl 6)
14. McNamara C, Davies J, Dyer M, et al: Guidelines on the investigation and
management of follicular lymphoma. Br J Haematol 156:446-467, 2012
15. Zelenetz AD, Abramson JS, Advani RH, et al: Non-Hodgkins lymphomas.
J Natl Compr Cancer Netw 9:484-560, 2011
16. Buch MH, Smolen JS, Betteridge N, et al: Updated consensus statement on
the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2011
17. Lee R, Vu K, Bell CM, et al: Screening for hepatitis B surface antigen before
chemotherapy: Current practice and opportunities for improvement. Current
Oncology 17:32-38, 2010
18. Day FL, Link E, Thursky K, et al: Current hepatitis B screening practices and
clinical experience of reactivation in patients undergoing chemotherapy for solid
tumors: A nationwide survey of medical oncologists. J Oncol Pract 7:141-147, 2011
19. Mendez-Navarro J, Corey KE, Zheng H, et al: Hepatitis B screening,
prophylaxis and re-activation in the era of rituximab-based chemotherapy. Liver
International 31:330-339, 2011
20. Day FL, Karnon J, Rischin D: Cost-effectiveness of universal hepatitis B
virus screening in patients beginning chemotherapy for solid tumors. J Clin Oncol
29:3270-3277, 2011
21. Targhetta C, Cabras MG, Mamusa AM, et al: Hepatitis B virus-related liver
disease in isolated anti-hepatitis B-core positive lymphoma patients receiving
chemo- or chemo-immune therapy. Haematologica 93:951-952, 2008
22. Haller DG, Cox JV: Provisional clinical opinion. J Clin Oncol 27:1925, 2009
23. Lau GKK, Yiu HHY, Fong DYT, et al: Early is superior to deferred
preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology 125:1742-1749, 2003
24. Hsu C, Hsiung CA, Su IJ, et al: A revisit of prophylactic lamivudine for
chemotherapy-associated hepatitis B reactivation in non-Hodgkins lymphoma: A
randomized trial. Hepatology 47:844-853, 2008
25. Dai MS, Chao TY, Kao WY, et al: Delayed hepatitis B virus reactivation after
cessation of preemptive lamivudine in lymphoma patients treated with rituximab
plus CHOP. Ann Hematol 83:769-774, 2004
26. Garcia-Rodriguez MJ, Canales MA, Hernandez-Maraver D, et al: Late
reactivation of resolved hepatitis B virus infection: An increasing complication
post rituximab-based regimens treatment? Am J Hematol 83:673-675, 2008
27. Allen MI, Deslauriers M, Andrews CW, et al: Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Hepatology
27:1670-1677, 1998

DOI: 10.1200/JCO.2012.43.7509; published online ahead of print at

www.jco.org on August 13, 2012

www.jco.org

2012 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on December 22, 2014. For personal use only. No other uses without permission.
Copyright 2012 American Society of Clinical Oncology. All rights reserved.

3157