Drug information response for IPPE-3 Experience (Oncology)

1. IPPE-3 DRUG INFORMATION (SHORT) RESPONSE DOCUMENTATION
Rotation Dates: February 20th
-April 2nd
Type of Rotation: Outpatient Oncology
Preceptor Name: Eugene Przespolewski Student Name: Geoffrey Brown
Date of Question: March 3rd
, 2017 Date of Response: March 16th
, 2017
SpecificQuestion: Whenshould patients receiving rituximab be screenedfor hepatitis B virus? What screening
tests should be utilized, and if positive what prophylaxis is recommended and for how long (optimal duration of
therapy)?
Type of Question: Short Answer (single-spaced)
Type of Short Answer Question: Controversial Literature Evaluation
This is graded document is draft #___ (preceptor to complete)
Preceptor Signature Date
Response/ Literature Review:
Rituximab or Rituxan ® is a CD-20 directed monoclonal antibody (MAB) approved for the treatment of Non-
Hodgkin lymphoma. After binding to CD-20 on B-cells, rituximab causes cell lysis through what is believed to
be a complement dependent or antibody mediated mechanism [1]. In 2013, 7 years after approval, the Food &
Drug Administration (FDA) required a black box warning for hepatitis B virus (HBV) reactivation be added to
rituximab and ofatumumab (another CD-20 directed MAB) labels. This change came after review of the FDA’s
Adverse Event Reporting System (AERS) revealed 109 cases of fatal HBV related acute liver injury.
Of the 109 cases reported, 106 cases occurred in patients treated with rituximab [2]. The mechanism by which
rituximab causes HBV reactivation is poorly understood. One theory is that B-cell depletion caused by
rituximab leads to a decrease in antigen presentation to CD-8 positive cytotoxic T-cells. Then, the absence of
T-cell recognition gives the HBV an opportunity to replicate. HBV replication alone does not cause damage to
hepatocytes. Rather, it is the host immune response that is responsible for hepatocellular damage and
inflammation [3,4].
There are four serologic tests used for HBV screening. Hepatitis B surface antigen (HBsAg) is a protein on the
outer surface of the HBV. When present, HBsAg is indicative of either an acute or chronic infection and
signifies the patient is infectious. The antibody to the HBV surface antigen (anti-HBs) is positive in persons
immune to HBV. Patients positive for anti-HBs have either recovered from an actual HBV infection or have
been effectively immunized against HBV. The hepatitis B core antibody (anti-HBc) is present after symptoms
develop from an acute HBV infection. Once a patient develops antibodies to the HBV core they will stay
positive for anti-HBc for life. The last screening test used is the Immunoglobulin-M anti-HBc (IgM anti-HBc)
test. This test is indicative of HBV infection within 6 months. Patients testing positive for IgM anti-HBc are
acutely infected with HBV [5]. A negative test result for all four serologic markers indicates susceptibility to
HBV infection and patients should be immunized. If a patient is positive for both anti-HBs and anti-HBc, they
are immune due to a natural infection. Whereas patients positive for only anti-HBs received immunity through
vaccination. If a patient is triple positive for HBsAg, anti-HBc, and IgM anti-HBc they are acutely infected. On
the other hand, chronic infection is indicated by testing positive for both HBsAg and anti-HBc. A harder result
to interpret, is a positive result for anti-HBc with negative HBsAg and negative anti-HBs. This could mean a
patient has a previously resolved HBV infection or a chronic infection with low viral activity [3,5].
Multiple liver societies (APASL & EASL), the Center for Disease Control (CDC) as well as the American
Society for Clinical Oncology (ASCO) have recommended universal screening for presence of HBsAg and anti-
HBc prior to initiating rituximab [6-9]. In patients’ positive for anti-HBc and negative for HBsAg, the ASCO
recommends testing HBV-DNA and Alanine aminotransferase (ALT) every 3 months to monitor for reactivation.

2. In these patients, providers have the option to either initiate prophylaxis concurrently with rituximab or to initiate
antiviral therapy when a rise in HBV-DNA or ALT is detected [8]. However, prophylaxis started before
immunosuppressive therapy is proven to be more effective at preventing HBV reactivation than initiating
therapy at the first rise in HBV-DNA or ALT [10,16].
Lamivudine is a nucleoside analogue reverse transcriptase inhibitor with approval for treatment of chronic HBV
[11]. Lamivudine has been widely used for HBV prophylaxis in the setting of immunosuppression and has
been proven to reduce HBV reactivation, especially when initiated prior to start of chemotherapy [11,12].
Entecavir is another, more potent, nucleoside analogue reverse transcriptase inhibitor with approval to treat
HBV [13]. Recent studies have compared the effectiveness of Entecavir HBV prophylaxis to prophylaxis with
lamivudine [14,15]. The first study by Huang et al. [14], was a prospective randomized study in treatment
naïve, HBsAg positive, patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and
prednisone (R-CHOP) for diffuse large B-cell lymphoma. The study compared rates of HBV related hepatitis,
HBV reactivation, and chemotherapy disruption due to hepatitis, in patients taking either 0.5 mg entecavir or
100mg lamivudine, oral daily for 6 months. The rate of HBV was 15.1% less in the entecavir group, odds ratio
(OR) of 0.29 and 95% confidence interval (CI) (0.10-0.88) P value=.02. Rates of HBV reactivation were also
lower occurring 23.4% less in the entecavir group, OR 0.16 95% CI (0.05-0.52) P value =.001. Chemotherapy
disruption also occurred at a lesser rate in the entecavir group, 16.7% difference OR 0.07 95% CI (0.01-0.60)
P value = .002. The second study, by Chen and colleagues [15] was a retrospective cohort study of patients
with solid tumors undergoing systemic cytotoxic chemotherapy (SCC). This study examined HBV reactivation,
liver decompensation associated with HBV, and disruption of SCC in patients taking either 0.5 mg entecavir or
100mg lamivudine oral daily. No patients in the entecavir group (0/70), while 7% (10/143) of patients in the
lamivudine group experienced HBV reactivation (P=.01). Hepatitis was noted in 2 patients (5.9%) in the
entecavir group and 8 patients (12.9%) in the lamivudine group (P=0.5). Disruption of chemotherapy due to
hepatitis occurred in 1 patient (2.9%) in entecavir group and 6 patients (9.7%) in the lamivudine group (P =
0.4). This study was limited by characteristic differences between the study groups, differing durations of
prophylaxis between the groups (longer average duration seen in the entecavir group), retrospective nature,
and selection bias. Tenofovir is another high potency anti-viral similar to entecavir. A recent meta-analysis
examining 28 studies, found that prophylaxis with tenofovir was the most effective at preventing HBV
reactivation, followed by entecavir [17].
The duration of prophylaxis is important because B-cell depletion following rituximab therapy can persist for
months after the drug is discontinued [1]. The ASCO recommends continuing prophylaxis for 12 months after
the drug is stopped [8]. However, the decision for how long to continue prophylactic anti-viral therapy probably
depends on the drug being utilized and should be a collaborative decision made by both cancer and liver
experts [8]. Two studies have found no HBV reactivation in patients treated with prophylactic entecavir for 6
months after chemotherapy cessation [14,16].

3. References:
1. Rituxan ® [package insert]. Genentech, Inc., San Francisco CA: April 2016
<https://www.gene.com/download/pdf/rituxan_prescribing.pdf>Accessed: 15 Mar. 2017.
2. Center for Drug Evaluation and Research. "Drug Safety and Availability - FDA Drug Safety
Communication: Boxed Warning and New Recommendations to Decrease Risk of Hepatitis B Reactivation
with the Immune-suppressing and Anti-cancer Drugs Arzerra (ofatumumab) and Rituxan (rituximab)." U S
Food and Drug Administration Home Page. Center for Drug Evaluation and Research, 25 Sept. 2013. Web. 20
Mar. 2017. <https://www.fda.gov/Drugs/DrugSafety/ucm366406.htm#tabs-2>.
3. Martin, S. T., S. M. Cardwell, M. D. Nailor, and S. Gabardi. "Hepatitis B Reactivation and Rituximab: A
New Boxed Warning and Considerations for Solid Organ Transplantation."American Journal of
Transplantation 14.4 (2014): 788-96. Web. 20 Mar. 2017.
4. Sprengers, Dave, Renate G. Van Der Molen, Johannes G. Kusters, Robert A. De Man, Hubert G.m.
Niesters, Solko W. Schalm, and Harry L.a. Janssen. "Analysis of Intrahepatic HBV-specific Cytotoxic T-cells
during and after Acute HBV Infection in Humans." Journal of Hepatology 45.2 (2006): 182-89. Web.
5. Advisory Committee on Immunization Practices. "Interpretation of Hepatitis B Serologic Test
Results." Cdc.gov. Division of Viral Hepatitis, Web. 20 Mar. 2017.
<https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf>.
6. Sarin, S. K. "Asian-Pacific Clinical Practice Guidelines on the Management of Hepatitis B: A 2015
Update." Hepatology International 10 (2016): 1-98. Springer. Web. 15 Mar. 2017. <http://apasl.info/apasl-hbv-
guideline-2016.pdf>.
7. Morbidity and Mortality Weekly Report. Vol. 57. Recommendations and Reports ed. 8.
“Recommendations for Identification and Public Health Management of Persons with Chronic Hepatitis B Virus
Infection.” Department of Health and Human Services, Center for Disease Control. Web. 15 Mar. 2017.
<https://www.cdc.gov/mmwr/PDF/rr/rr5708.pdf>.
8. Hwang, Jessica P., Mark R. Somerfield, Devena E. Alston-Johnson, Donna R. Cryer, Jordan J. Feld,
Barnett S. Kramer, Anita L. Sabichi, Sandra L. Wong, and Andrew S. Artz. "Hepatitis B Virus Screening for
Patients with Cancer Before Therapy: American Society of Clinical Oncology Provisional Clinical Opinion
Update." Journal of Clinical Oncology 33.19 (2015): 2212-220. Web. 15 Mar. 2017.
9. EASL Clinical Practice Guidelines: Management of Chronic Hepatitis B." Journal of Hepatology 50.2
(2009): 227-42. Web. 20 Mar. 2017.
10. Lau, George K.k, Harry H.y Yiu, Daniel Y.t Fong, Hoi-Ching Cheng, Wing-Yan Au, Lydia S.f Lai,
Micheal Cheung, Hai-Ying Zhang, Albert Lie, Roger Ngan, and Raymond Liang. "Early Is Superior to Deferred
Preemptive Lamivudine Therapy for Hepatitis B Patients Undergoing Chemotherapy." Gastroenterology 125.6
(2003): 1742-749.
11. EPIVIR HBV ® [package insert]. GlaxoSmithKline, Inc., Research Triangle Park, NC: December
2013<https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Epivir
-HBV/pdf/EPIVIR-HBV-PI-PIL.PDF> Accessed: 20 Mar. 2017.
12. Jang, Jeong Won, Jong Young Choi, Si Hyun Bae, Seung Kew Yoon, U. Im Chang, Chang Wook Kim,
Se Hyun Cho, Jun Yeol Han, and Young Sok Lee. "A Randomized Controlled Study of Preemptive Lamivudine
in Patients Receiving Transarterial Chemo-lipiodolization." Hepatology 43.2 (2006): 233-40. Web.
13. Zoulim F. Hepatitis B virus resistance to antiviral drugs: where are we going? Liver International.
2011;31 Suppl 1:111-116. doi:10.1111/j.1478-3231.2010.02399.x.

4. 14. Huang, He, Xueying Li, Jun Zhu, Sheng Ye, Hongyu Zhang, Wei Wang, Xiangyuan Wu, Jiewen Peng,
Bing Xu, Yingcheng Lin, Yabing Cao, Haoran Li, Suxia Lin, Qing Liu, and Tongyu Lin. "Entecavir vs
Lamivudine for Prevention of Hepatitis B Virus Reactivation Among Patients With Untreated Diffuse Large B-
Cell Lymphoma Receiving R-CHOP Chemotherapy." Jama 312.23 (2014): 2521. Web. 16 Mar. 2017.
<http://jamanetwork.com/journals/jama/fullarticle/2040216>.
15. Chen W-C, Cheng J-S, Chiang P-H, Tsay F-W, Chan H-H, Chang H-W, et al. (2015) A Comparison of
Entecavir and Lamivudine for the Prophylaxis of Hepatitis B Virus Reactivation in Solid Tumor Patients
Undergoing Systemic Cytotoxic Chemotherapy. PLoS ONE 10(6): e0131545.
doi:10.1371/journal.pone.0131545
16. Huang, Yi-Hsiang, Liang-Tsai Hsiao, Ying-Chung Hong, Tzeon-Jye Chiou, Yuan-Bin Yu, Jyh-Pyng
Gau, Chun-Yu Liu, Muh-Hwa Yang, Cheng-Hwai Tzeng, Pui-Ching Lee, Han-Chieh Lin, and Shou-Dong Lee.
"Randomized Controlled Trial of Entecavir Prophylaxis for Rituximab-Associated Hepatitis B Virus Reactivation
in Patients With Lymphoma and Resolved Hepatitis B." Journal of Clinical Oncology 31.22 (2013): 2765-772.
Web.
17. Zhang, Min-Yue, Gui-Qi Zhu, Ji-Na Zheng, Zhang Cheng, Sven Van Poucke, Ke-Qing Shi, Hong-Hui
Huang, Fang-Yuan Chen, and Ming-Hua Zheng. "Nucleos(t)ide Analogues for Preventing HBV Reactivation in
Immunosuppressed Patients with Hematological Malignancies: A Network Meta-analysis." Expert Review of
Anti-infective Therapy (2017): n. pag. Web.