Key Points
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Imprecision surrounding the nomenclature of HBV reactivation has contributed to confusion regarding its incidence; standardization of terminology and definitions are needed
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Patients positive for hepatitis B surface antigen (HBsAg) and those who are HBsAg-negative and anti-HBc (hepatitis B core antibody IgG)-positive are at risk of HBV reactivation during immunosuppressive therapies
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Level of risk of HBV reactivation depends not only on the serological profile of the patient, but also their underlying medical conditions and the immunosuppressive therapies that will be used
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Strong evidence exists to support antiviral prophylaxis to prevent reactivation of HBV infection; in general, HBsAg-positive patients should be started on antiviral prophylaxis before immunosuppression
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HBsAg-negative–anti-HBc-positive patients receiving immunosuppressive therapy might be monitored unless they are considered for certain therapies (such as anti-CD20 antibodies), in which case, these patients should receive antiviral prophylaxis
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Screening for HBV prior to the start of immunosuppressive therapy is the key to preventing reactivation of HBV infection
Abstract
Patients with chronic HBV infection are at risk of reactivation of HBV should they require immunosuppressive therapies for a variety of clinical settings, including chemotherapy for patients with cancer, immunosuppression for solid organ and stem cell transplant recipients, and use of anti-CD20 antibodies, TNF inhibitors, or corticosteroids in patients with oncological, gastrointestinal, rheumatological or dermatological conditions. The key to preventing HBV reactivation is the identification of patients with HBV infection prior to immunosuppressive therapy, initiation of prophylactic antiviral therapy in patients at moderate or high risk of HBV reactivation, and close monitoring of other patients so that antiviral therapy can be initiated at the first sign of HBV reactivation. Unfortunately, many patients infected with HBV are unaware of their infection or risk factors, and physicians often do not have sufficient time to systematically assess patients for risk factors for HBV prior to starting immunosuppressive therapy. In this article, we review the incidence, risk factors and outcomes of HBV reactivation, and the efficacy of antiviral therapy in preventing its occurrence. We also propose an algorithm for managing patients with HBV infection who require immunosuppressive therapy.
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References
Keam, B., Lee, J. H., Im, S. A. & Yoon, J. H. Why, when, and how to prevent hepatitis B virus reactivation in cancer patients undergoing chemotherapy. J. Natl Compr. Canc. Netw. 9, 465–477 (2011).
Vassilopoulos, D. & Calabrese, L. H. Management of rheumatic disease with comorbid HBV or HCV infection. Nat. Rev. Rheumatol. 8, 348–357 (2012).
Chan, T. M. et al. Preemptive lamivudine therapy based on HBV DNA level in HBsAg-positive kidney allograft recipients. Hepatology 36, 1246–1252 (2002).
Vigano, M., Degasperi, E., Aghemo, A., Lampertico, P. & Colombo, M. Anti-TNF drugs in patients with hepatitis B or C virus infection: Safety and clinical management. Expert Opin. Biol. Ther. 12, 193–207 (2012).
Hoofnagle, J. H. Reactivation of hepatitis B. Hepatology 49, S156–S165 (2009).
Loomba, R. et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann. Intern. Med. 148, 519–528 (2008).
Tran, T. T., Rakoski, M. O., Martin, P. & Poordad, F. Screening for hepatitis B in chemotherapy patients: survey of current oncology practices. Aliment. Pharmacol. Ther. 31, 240–246 (2010).
Day, F. L., Link, E., Thursky, K. & Rischin, D. 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).
Weinbaum, C. M. et al. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm. Rep. 57, 1–20 (2008).
EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J. Hepatol. 57, 167–185 (2012).
Liaw, Y. F. et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: A 2012 update. Hepatol. Int. 6, 531–561 (2012).
Lok, A. S. F. & McMahon, B. J. AASLD practice guideline update: chronic hepatitis B: update 2009. Hepatology 50, 661–662 (2009).
Artz, A. S. 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).
Baden, L. R. et al. Prevention and treatment of cancer-related infections. J. Natl Compr. Canc. Netw. 10, 1412–1445 (2012).
Chu, C. J., Hussain, M. & Lok, A. S. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. Hepatology 36, 1408–1415 (2002).
Fong, T. L., Di Bisceglie, A. M., Gerber, M. A., Waggoner, J. G. & Hoofnagle, J. H. Persistence of hepatitis B virus DNA in the liver after loss of HBsAg in chronic hepatitis B. Hepatology 18, 1313–1318 (1993).
Rehermann, B., Ferrari, C., Pasquinelli, C. & Chisari, F. V. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat. Med. 2, 1104–1108 (1996).
Huang, Y. H. 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. 31, 2765–2772 (2013).
Hsu, C. et al. Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study. Hepatology http://dx.doi.org/10.1002/hep.26718.
Chang, J. J. & Lewin, S. R. Immunopathogenesis of hepatitis B virus infection. Immunol. Cell Biol. 85, 16–23 (2007).
Tur-Kaspa, R., Burk, R. D., Shaul, Y. & Shafritz, D. A. Hepatitis B virus DNA contains a glucocorticoid-responsive element. Proc. Natl Acad. Sci. USA 83, 1627–1631 (1986).
Carroll, M. B. & Forgione, M. A. Use of tumor necrosis factor alpha inhibitors in hepatitis B surface antigen-positive patients: a literature review and potential mechanisms of action. Clin. Rheumatol. 29, 1021–1029 (2010).
Lalazar, G., Rund, D. & Shouval, D. Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies. Br. J. Haematol. 136, 699–712 (2007).
Lok, A. S. et al. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology 100, 182–188 (1991).
Evens, A. M. et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann. Oncol. 22, 1170–1180 (2011).
Hammond, S. P. et al. Hepatitis B virus reactivation following allogeneic hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 15, 1049–1059 (2009).
Yeo, W. et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J. Med. Virol. 62, 299–307 (2000).
Yeo, W. et al. Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy. Ann. Oncol. 15, 1661–1666 (2004).
Jang, J. W. et al. A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization. Hepatology 43, 233–240 (2006).
Hui, C. K. et al. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology 131, 59–68 (2006).
Hsiao, L.-T. et al. Extended lamivudine therapy against hepatitis B virus infection in hematopoietic stem cell transplant recipients. Biol. Blood Marrow Transplant. 12, 84–94 (2006).
American Association for the Study of Liver Diseases Emerging Trends Conference, Reactivation of Hepatitis B March 21–22, 2013; Arlington, VA (2013).
Yeo, W. et al. Hepatitis B virus reactivation in breast cancer patients receiving cytotoxic chemotherapy: a prospective study. J. Med. Virol. 70, 553–561 (2003).
Yun, J. et al. Prophylactic use of lamivudine for hepatitis B exacerbation in post-operative breast cancer patients receiving anthracycline-based adjuvant chemotherapy. Br. J. Cancer 104, 559–563 (2011).
Yeo, W. et al. Comprehensive analysis of risk factors associating with hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br. J. Cancer 90, 1306–1311 (2004).
Llovet, J. M. & Bruix, J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 37, 429–442 (2003).
Cescon, M., Cucchetti, A., Ravaioli, M. & Pinna, A. D. Hepatocellular carcinoma locoregional therapies for patients in the waiting list. Impact on transplantability and recurrence rate. J. Hepatol. 58, 609–618 (2013).
Golfieri, R. et al. Efficacy of selective transarterial chemoembolization in inducing tumor necrosis in small (<5 cm) hepatocellular carcinomas. Hepatology 53, 1580–1589 (2011).
Lao, X.-M. et al. Changes in hepatitis B virus DNA levels and liver function after transcatheter arterial chemoembolization of hepatocellular carcinoma. Hepatol. Res. 41, 553–563 (2011).
Gupta, V., Lazarus, H. M. & Keating, A. Myeloablative conditioning regimens for AML allografts: 30 years later. Bone Marrow Transplant. 32, 969–978 (2003).
Wahid, S. F. Indications and outcomes of reduced-toxicity hematopoietic stem cell transplantation in adult patients with hematological malignancies. Int. J. Hematol. 97, 581–598 (2013).
Lau, G. K., Liang, R., Chiu, E. K., Lee, C. K. & Lam, S. K. Hepatic events after bone marrow transplantation in patients with hepatitis B infection: a case controlled study. Bone Marrow Transplant. 19, 795–799 (1997).
Park, S. et al. Changes of hepatitis B virus serologic status after allogeneic hematopoietic stem cell transplantation and impact of donor immunity on hepatitis B virus. Biol. Blood Marrow Transplant. 17, 1630–1637 (2011).
Seth, P. et al. Hepatitis B virus reactivation with clinical flare in allogeneic stem cell transplants with chronic graft-versus-host disease. Bone Marrow Transplant. 30, 189–194 (2002).
Vigano, M. et al. Risk of hepatitis B surface antigen seroreversion after allogeneic hematopoietic SCT. Bone Marrow Transplant. 46, 125–131 (2011).
Ramos, C. A. et al. Resolved hepatitis B virus infection is not associated with worse outcome after allogeneic hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 16, 686–694 (2010).
Liu, C. J. et al. Lamivudine treatment for hepatitis B reactivation in HBsAg carriers after organ transplantation: a 4-year experience. J. Gastroenterol. Hepatol. 16, 1001–1008 (2001).
Dusheiko, G. et al. Natural history of hepatitis B virus infection in renal transplant recipients—a fifteen-year follow-up. Hepatology 3, 330–336 (1983).
Mathurin, P. et al. Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology 29, 257–263 (1999).
Kalia, H., Fabrizi, F. & Martin, P. Hepatitis B virus and renal transplantation. Transplant. Rev. (Orlando) 25, 102–109 (2011).
Berger, A., Preiser, W., Kachel, H. G., Sturmer, M. & Doerr, H. W. HBV reactivation after kidney transplantation. J. Clin. Virol. 32, 162–165 (2005).
Chen, G. D., Gu, J. L., Qiu, J. & Chen, L. Z. Outcomes and risk factors for hepatitis B virus (HBV) reactivation after kidney transplantation in occult HBV carriers. Transpl. Infect. Dis. 15, 300–305 (2013).
Grossi, P. et al. Prevalence and outcome of hepatitis B virus (HBV) infection following thoracic organ transplantation. J. Heart Lung Transplant. 20, 179 (2001).
Lunel, F. et al. Hepatitis virus infections in heart transplant recipients: epidemiology, natural history, characteristics, and impact on survival. Gastroenterology 119, 1064–1074 (2000).
Shitrit, A. B. et al. Lamivudine prophylaxis for hepatitis B virus infection after lung transplantation. Ann. Thorac. Surg. 81, 1851–1852 (2006).
Zampino, R. et al. Heart transplantation in patients with chronic hepatitis B: clinical evolution, molecular analysis, and effect of treatment. Transplantation 80, 1340–1343 (2005).
Gea-Banacloche, J. C. Rituximab-associated infections. Semin. Hematol. 47, 187–198 (2010).
Yeo, W. 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).
US Department of Health and Human Services. Product approval information—licensing action. US Food and Drug Administration [online], (1997).
US Department of Health and Human Services. Approval history for arzerra. US Food and Drug Administration [online], (2009).
Nayernama, A. et al. Hepatitis B virus reactivation in CD20 antibody-treated patients: evaluation of post-market data from the FDA adverse event reporting system [abstract #8]. Presented at the American Association for the Study of Liver Diseases Emerging Trends Conference: Reactivation of Hepatitis B (2013).
US Department of Health and Human Services. 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). US Food and Drug Administration [online], (2013).
US Department of Health and Human Services. Label information for rituximab. US Food and Drug Administration [online], (2013).
US Department of Health and Human Services. Label information for ofatumumab. US Food and Drug Administration [online], (2013).
Iannitto, E. et al. Hepatitis B virus reactivation and alemtuzumab therapy. Eur. J. Haematol. 74, 254–258 (2005).
Moses, S. E. et al. Lamivudine prophylaxis and treatment of hepatitis B Virus-exposed recipients receiving reduced intensity conditioning hematopoietic stem cell transplants with alemtuzumab. J. Med. Virol. 78, 1560–1563 (2006).
Perez-Alvarez, R. et al. Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases. Medicine (Baltimore) 90, 359–371 (2011).
Scullard, G. H., Smith, C. I., Merigan, T. C., Robinson, W. S. & Gregory, P. B. Effects of immunosuppressive therapy on viral markers in chronic active hepatitis B. Gastroenterology 81, 987–991 (1981).
Hoofnagle, J. H. et al. A short course of prednisolone in chronic type B hepatitis. Report of a randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 104, 12–17 (1986).
Sheen, I. S., Liaw, Y. F., Lin, S. M. & Chu, C. M. Severe clinical rebound upon withdrawal of corticosteroid before interferon therapy: incidence and risk factors. J. Gastroenterol. Hepatol. 11, 143–147 (1996).
Cheng, A. L. et al. Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma. Hepatology 37, 1320–1328 (2003).
Flowers, M. A. et al. Fulminant hepatitis as a consequence of reactivation of hepatitis B virus infection after discontinuation of low-dose methotrexate therapy. Ann. Intern. Med. 112, 381–382 (1990).
Droz, N. et al. Kinetic profiles and management of hepatitis B virus reactivation in patients with immune-mediated inflammatory diseases. Arthritis Care Res. (Hoboken) 65, 1504–1514 (2013).
Liang, R. H. et al. Hepatitis B infection in patients with lymphomas. Hematol. Oncol. 8, 261–270 (1990).
Yeo, W. & Chan, H. L. Hepatitis B virus reactivation associated with anti-neoplastic therapy. J. Gastroenterol. Hepatol. 28, 31–37 (2013).
Hsu, C. H. et al. Doxorubicin activates hepatitis B virus (HBV) replication in HBV-harboring hepatoblastoma cells. A possible novel mechanism of HBV reactivation in HBV carriers receiving systemic chemotherapy. Anticancer Res. 24, 3035–3040 (2004).
Lau, G. K. et al. High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation. Blood 99, 2324–2330 (2002).
Ferraro, D. et al. Evaluating the risk of hepatitis B reactivation in patients with haematological malignancies: is the serum hepatitis B virus profile reliable? Liver Int. 29, 1171–1177 (2009).
Kanaan, N. et al. Significant rate of hepatitis B reactivation following kidney transplantation in patients with resolved infection. J. Clin. Virol. 55, 233–238 (2012).
Onozawa, M. et al. Progressive disappearance of anti-hepatitis B surface antigen antibody and reverse seroconversion after allogeneic hematopoietic stem cell transplantation in patients with previous hepatitis B virus infection. Transplantation 79, 616–619 (2005).
Colvin, H. M. & Mitchel, A. E. Hepatitis and Liver Cancer: a National Strategy for Prevention and Control of Hepatitis B and C (National Academies Press, 2010).
Hatzakis, A. et al. The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference. J. Viral Hepat. 18 (Suppl. 1), 1–16 (2011).
Hwang, J. P. et al. Low rates of hepatitis B virus screening at the onset of chemotherapy. J. Oncol. Pract. 8, e32–e39 (2012).
McQuillan, G. M. et al. Prevention of perinatal transmission of hepatitis B virus: the sensitivity, specificity, and predictive value of the recommended screening questions to detect high-risk women in an obstetric population. Am. J. Epidemiol. 126, 484–491 (1987).
Lau, G. K. et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology 125, 1742–1749 (2003).
Hsu, C. et al. A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin's lymphoma: a randomized trial. Hepatology 47, 844–853 (2008).
Lan, J. L. et al. Kinetics of viral loads and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumour necrosis factor alpha therapy. Ann. Rheum. Dis. 70, 1719–1725 (2011).
Vassilopoulos, D. et al. Long-term safety of anti-TNF treatment in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection. Ann. Rheum. Dis. 69, 1352–1355 (2010).
Marcellin, P. et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 381, 468–475 (2013).
Tenney, D. J. et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology 49, 1503–1514 (2009).
Kearney, B. P., Flaherty, J. F. & Shah, J. Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. Clin. Pharmacokinet. 43, 595–612 (2004).
Weiss, J., Weis, N., Ketabi-Kiyanvash, N., Storch, C. H. & Haefeli, W. E. Comparison of the induction of P-glycoprotein activity by nucleotide, nucleoside, and non-nucleoside reverse transcriptase inhibitors. Eur. J. Pharmacol. 579, 104–109 (2008).
Cooper, R. D. et al. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin. Infect. Dis. 51, 496–505 (2010).
Li, H. R. et al. Comparison of entecavir and lamivudine in preventing hepatitis B reactivation in lymphoma patients during chemotherapy. J. Viral Hepat. 18, 877–883 (2011).
Matsue, K. et al. Reactivation of hepatitis B virus after rituximab-containing treatment in patients with CD20-positive B-cell lymphoma. Cancer 116, 4769–4776 (2010).
Fung, J. et al. Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation. Gastroenterology 141, 1212–1219 (2011).
Hui, C. K. et al. Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy. Gut 54, 1597–1603 (2005).
Dai, M. S., Chao, T. Y., Kao, W. Y., Shyu, R. Y. & Liu, T. M. Delayed hepatitis B virus reactivation after cessation of preemptive lamivudine in lymphoma patients treated with rituximab plus CHOP. Ann. Hematol. 83, 769–774 (2004).
Noterdaeme, T. et al. Liver transplantation for acute hepatic failure due to chemotherapy-induced HBV reactivation in lymphoma patients. World J. Gastroenterol. 17, 3069–3072 (2011).
Acknowledgements
The authors acknowledge Laurissa Gann for assistance with the literature search. The work of A. S.-F. Lok is partially funded by a National Institute of Diabetes and Digestive and Kidney Diseases grant U01DK082863. J. P. Hwang is a recipient of a National Cancer Institute (NCI) KO7 Career Development Award (CA132955) and NCI R21 (CA167202). The content of this Review is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
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A. S.-F. Lok is a consultant and/or advisor to GlaxoSmithKline, Gilead, and Novartis, and she has grant funding from Gilead and Bristol-Myers Squibb. J. P. Hwang declares no competing interests.
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Hwang, J., Lok, AF. Management of patients with hepatitis B who require immunosuppressive therapy. Nat Rev Gastroenterol Hepatol 11, 209–219 (2014). https://doi.org/10.1038/nrgastro.2013.216
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DOI: https://doi.org/10.1038/nrgastro.2013.216
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