The incidence of both hepatitis B virus infection and cancer is common. The use of immunosuppressive therapy in patients with hepatitis B virus can result in reactivation of hepatitis B virus, which can, in turn, lead to significant morbidity and mortality.
Hepatitis B virus (HBV) infection is common across the world. Infection can lead to significant morbidity from cirrhosis and hepatocellular carcinoma. An estimated 240 million people have chronic (hepatitis B surface antigen [HBsAg]-positive) HBV infection. As a result of increasing immigration from highly endemic areas (eg, China, Southeast Asia, Africa, Eastern Europe), the prevalence of chronic infection in the United States is rising and is estimated to be 1.5 million. Across the country, the overall age-adjusted prevalence of chronic infection and evidence of exposure to infection (defined by the presence of antibody to HBV core antigen [anti-HBc] in the absence of HBsAg) have been reported to be 0.3% and 4.7%, respectively; however, rates are much higher and can approach 10% to 15% in certain cities. In addition, many patients with HBV infection are unaware that they are infected.[4,5] At the same time, it is estimated that over 40% of the US population will develop some type of cancer during their lifetime, and most patients will receive immunosuppressive therapy (IST) as treatment for their malignancy. This is notable because patients with chronic HBV infection or evidence of prior HBV infection who are exposed to IST are at risk for HBV reactivation.[7,8] We will discuss HBV reactivation in order to raise awareness of the problem and to detail our strategy for preventing this potentially severe complication of IST.
Screening patients for HBV and intervening with appropriate antiviral prophylaxis prior to IST prevents HBV reactivation and its morbid sequelae. The definition of HBV reactivation varies, but we define viral reactivation as the reappearance of detectable HBV DNA that had been previously undetectable, or a positive HBsAg and HBV DNA level > 10,000 IU/mL in a previously unscreened patient. HBV can lead to hepatitis, which is defined as a threefold increase in alanine aminotransferase from baseline value. Hepatitis may then lead to impairment of liver function, liver failure, and death.[7,9] HBV reactivation can result in delay or termination of curative oncologic treatment, which may increase a patient’s risk of mortality.
There is variability in the approach to HBV screening before cancer therapy. Some national guidelines[5,11] encourage universal screening of patients receiving cytotoxic therapy or IST, whereas others[12,13] support risk-based screening. Our current approach at Memorial Sloan Kettering Cancer Center (MSKCC) is to screen all new patients who will be receiving IST. Although certain patients may have a higher pre-test probability of a positive screening result (based on country of birth, sexual history, and blood transfusion, among other factors), our past experience at MSKCC has shown that at least half of HBV reactivations occurred in patients considered to be “low risk” for HBV infection; therefore, individualized risk-based screening would have missed these patients. Although HBV reactivation was initially described in lymphoma patients and best documented in HBsAg-positive patients treated with IST for hematologic malignancies,[14,15] the risk is not confined to this group; patients with solid tumors have also had documented HBV reactivation.[10,16,17] B-cell–depleting therapies and hematopoietic stem cell transplant (HSCT) are associated with higher risk of HBV reactivation.[8,18-21] For example, patients with previous exposure to HBV can also experience HBV reactivation when receiving rituximab-based therapy.[22-24] HBV reactivation can occur anytime during and for at least 12 months after completion of IST in certain patient populations.[25,26]
After a thorough review of the literature and society guidelines,[12,13] our approach is to screen by testing for HBsAg and anti-HBc, with reflexive testing of HBV DNA by polymerase chain reaction (PCR) in patients with positive results on either test. A small proportion of patients with exposure to HBV alone can have circulating DNA, and they appear to be at higher risk for HBV reactivation than patients who are anti-HBc–positive with negative PCR results. Patients who are HBsAg-positive or have detectable hepatitis B (HB) viral load (VL) receive oral entecavir 0.5 mg daily through the course of chemotherapy and for at least 6 months after the completion of cancer treatment. In addition, patients who are HBsAg-negative/anti-HBc–positive with undetectable HB VL are given entecavir prophylaxis prior to anti-CD20 therapy or before undergoing HSCT. Otherwise, patients positive for anti-HBc alone undergo monitoring of HB VL every 3 months, with prompt administration of entecavir if the VL becomes detectable.
For patients who are HBsAg-positive/anti-HBc–positive, there is a well-documented role for antiviral prophylaxis during treatment of hematologic and solid tumor malignancies.[27-31] Although lamivudine is inexpensive and well-studied in the prophylactic setting, breakthrough treatment resistance is a problem, both with short- and long-term use.[32-34] Entecavir and tenofovir are potent HBV inhibitors with a high barrier to resistance and are therefore first-line agents. A recent randomized controlled trial found that when compared with lamivudine, entecavir significantly reduced the rate of HBV reactivation (6.6% vs 30%; P = .001) and HBV-related hepatitis (0% vs 13.3%; P = .003). Patients undergoing anti-CD20 therapy or HSCT who have had prior HBV exposure also benefit from antiviral prophylaxis. Huang et al conducted a randomized controlled trial that compared entecavir prophylaxis-starting before, during, and for 3 months after completion of chemotherapy-with deferred treatment (control group). During a mean 18-month follow-up period, 1 (2.4%) of 41 patients taking entecavir prophylaxis developed HBV reactivation compared with 7 (17.9%) of 39 control patients (P = .027). No patients developed HBV-related liver decompensation or mortality in this study.
Prophylaxis is maintained for at least 6 months after the completion of chemotherapy. Some guidelines recommend continuation for at least 12 months in patients receiving anti-CD20 therapy and HSCT.[12,13] The longer duration recommendation is a result of the discovery of HBV flares occurring up to 12 to 17 months after the last anti-CD20 dose.[36,37] This is certainly an area for further study.
The incidence of both HBV infection and cancer is common. The use of IST in patients with HBV can result in reactivation of HBV, which can, in turn, lead to significant morbidity and mortality. Although rates of HBV infection vary among populations, we feel that selective screening can miss a significant number of patients. We believe that our strategy of universal screening with HBsAg and anti-HBc prior to IST, followed by entecavir prophylaxis in all HBsAg-positive patients and selected HBsAg-negative/anti-HBc–positive patients, is effective and reasonable. Areas of uncertainty that require further investigation include evaluating the cost-effectiveness of universal pre-IST HBV screening, management of patients with solid tumors who are positive for anti-HBc only, and optimal duration of antiviral prophylaxis following completion of IST.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg sero-prevalence and endemicity. Vaccine. 2012;30:2212-9.
2. Kim WR. Epidemiology of hepatitis B in the United States. Hepatology. 2009;49:S28-S34.
3. Wasley A, Kruszon-Moran D, Kuhnert W, et al. The prevalence of hepatitis B virus infection in the United States in the era of vaccination. J Infect Dis. 2010;202:192-201.
4. US Department of Health and Human Services. Action plan for the prevention, care, and treatment of viral hepatitis: updated, 2014-2016. http://aids.gov/pdf/viral-hepatitis-action-plan.pdf. Accessed October 15, 2015.
5. Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57:1-20.
6. National Cancer Institute. Lifetime risk of being diagnosed with cancer by site and race/ethnicity. http://seer.cancer.gov/csr/1975_2012/results_merged/topic_lifetime_risk.pdf. Accessed October 20, 2015.
7. Lok AS, Liang RH, Chiu EK, et al. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology. 1991;100:182-8.
8. Evens AM, Jovanovic BD, Su YC, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol. 2011;22:1170-80.
9. Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology. 2006;43:209-20.
10. Liu JY, Sheng YJ, Ding XC, et al. The efficacy of lamivudine prophylaxis against hepatitis B reactivation in breast cancer patients undergoing chemotherapy: a meta-analysis. J Formos Med Assoc. 2015;114: 164-73.
11. National Comprehensive Cancer Network. Prevention and treatment of cancer-related infections. Version 1.2015. http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf. Accessed October 15, 2015.
12. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-2.
13. Hwang JP, Somerfield MR, Alston-Johnson DE, et al. Hepatitis B virus screening for patients with cancer before therapy: American Society of Clinical Oncology provisional clinical opinion update. J Clin Oncol. 2015;33:2212-20.
14. Oh MJ, Lee HJ. A study of hepatitis B virus reactivation associated with rituximab therapy in real-world clinical practice: a single-center experience. Clin Mol Hepatol. 2013;19:51-9.
15. Koo YX, Tay M, Teh YE, et al. Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/hepatitis B core antibody positive patients receiving rituximab-containing combination chemotherapy without routine antiviral prophylaxis. Ann Hematol. 2011; 90:1219-23.
16. Hagiwara S, Sakurai T, Nishina S, et al. Characteristic pattern of reactivation of hepatitis B virus during chemotherapy for solid cancers. Dig Dis. 2012;30:541-6.
17. Long M, Jia W, Li S, et al. A single-center, prospective and randomized controlled study: can the prophylactic use of lamivudine prevent hepatitis B virus reactivation in hepatitis B s-antigen seropositive breast cancer patients during chemotherapy? Breast Cancer Res Treat. 2011;127 :705-12.
18. Kim EB, Kim DS, Park SJ, et al. Hepatitis B virus reactivation in a surface antigen-negative and antibody-positive patient after rituximab plus CHOP chemotherapy. Cancer Res Treat. 2008;40:36-8.
19. Dong HJ, Ni LN, Sheng GF, et al. Risk of hepatitis B virus (HBV) reactivation in non-Hodgkin lymphoma patients receiving rituximab-chemotherapy: a meta-analysis. J Clin Virol. 2013;57:209-14.
20. Hammond SP, Borchelt AM, Ukomadu C, et al. Hepatitis B virus reactivation following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15:1049-59.
21. Papamichalis P, Alexiou A, Boulbou M, et al. Reactivation of resolved hepatitis B virus infection after immunosuppression: is it time to adopt pre-emptive therapy? Clin Res Hepatol Gastroenterol. 2012;36:84-93.
22. Yeo W, Chan TC, Leung NW, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol. 2009;27:605-11.
23. Koo YX, Tan DS, Tan IB, et al. Hepatitis B virus reactivation and role of antiviral prophylaxis in lymphoma patients with past hepatitis B virus infection who are receiving chemoimmunotherapy. Cancer. 2010; 116:115-21.
24. Matsue K, Kimura S, Takanashi Y, et al. Reactivation of hepatitis B virus after rituximab-containing treatment in patients with CD20-positive B-cell lymphoma. Cancer. 2010;116:4769-76.
25. Kohrt HE, Ouyang DL, Keeffe EB. Systematic review: lamivudine prophylaxis for chemotherapy-induced reactivation of chronic hepatitis B virus infection. Aliment Pharmacol Ther. 2006;24:1003-16.
26. Zachou K, Sarantopoulos A, Gatselis NK, et al. Hepatitis B virus reactivation in hepatitis B virus surface antigen negative patients receiving immunosuppression: a hidden threat. World J Hepatol. 2013;5:387-92.
27. Yeo W, Ho WM, Hui P, et al. Use of lamivudine to prevent hepatitis B virus reactivation during chemotherapy in breast cancer patients. Breast Cancer Res Treat. 2004;88:209-15.
28. Jang JW, Choi JY, Bae SH, et al. A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization. Hepatology. 2006;43:233-40.
29. Dai MS, Wu PF, Lu JJ, et al. Preemptive use of lamivudine in breast cancer patients carrying hepatitis B virus undergoing cytotoxic chemotherapy: a longitudinal study. Support Care Cancer. 2004;12:191-6.
30. Lau GK, Yiu HH, Fong DY, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology. 2003;125:1742-9.
31. Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med. 2008;148:519-28.
32. Papatheodoridis GV, Dimou E, Laras A, et al. Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease. Hepatology. 2002;36:219-26.
33. Hsu C, Hsiung CA, Su IJ, et al. A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin’s lymphoma: a randomized trial. Hepatology. 2008;47:844-53.
34. Tan YW, Ye Y, Ge GH, et al. Natural YMDD-motif mutants affect clinical course of lamivudine in chronic hepatitis B. World J Gastroenterol. 2015;21:2089-95.
35. Huang H, Li X, Zhu J, et al. Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial. JAMA. 2014;312:2521-30.
36. Huang YH, Hsiao LT, Hong YC, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol. 2013;31:2765-72.
37. US Food and Drug Administration. Boxed warning and new recommendations to decrease the risk of hepatitis B reactivation with the immune-suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab). http://www.fda.gov/Drugs/DrugSafety/ucm366406.htm. Accessed October 15, 2015.