Europe PMC Funders Group Author Manuscript Viral Hepat Pract. Author manuscript; available in PMC 2015 April 16. Published in final edited form as: Viral Hepat Pract. 2014 July 1; 6(1): 10–13.
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Hepatitis B and C prophylaxis in patients receiving chemotherapy Reina Lim, MB ChB MRCP [MRC Clinical Research Fellow and Senior Specialist Registrar] and Liver Research Laboratory, University of Birmingham Andrew Holt, PhD FRCP [Consultant Hepatologist] Department of Hepatology and Liver Transplantation, Queen Elizabeth Hospital, Edgbaston, Birmingham
Abstract
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Reactivation of infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) is defined as increased viral replication in patients with previously low-grade chronic infection. This may occur following the use of immunomodulatory therapy, chemotherapy or in response to severe illness. Most cases of HBV reactivation are asymptomatic; however, hepatic decompensation can occur in severe cases, where HBV reactivation is associated with a mortality of up to 30%.1 Over the last decade, it has been recognised that HBV reactivation can be effectively prevented by antiviral prophylaxis. In contrast, severe flares of hepatitis in response to HCV reactivation are less commonly reported and, when they occur, are associated with a much lower mortality. This article summarises the recent advances in this area and provides guidance for the management of HBV and HCV reactivation in patients undergoing chemotherapy.
HBV reactivation Prevalence of HBV infection The risk of HBV reactivation is influenced by the local prevalence of HBV. In 2002, the Department of Health estimated the prevalence of chronic HBV infection in adults in the UK to be 0.3% of the population.2 Other estimates have shown that the pool of chronically infected individuals may be as large as 375,000. These are almost certainly underestimates, as the last decade has seen unprecedented levels of migration across the world. It is estimated that 3% of the world’s population now lives outside their country of birth, Western Europe and North America being the most common destinations. In 2011, immigration to the UK reached 593,000 individuals per annum, 170,000 of whom had been born in new Commonwealth countries, where viral hepatitis is more prevalent than in the rest of the world.3
Copyright © Hayward Medical Communications 2014. All rights reserved. Declaration of interest Both authors declare that there is no conflict of interest. Dr Andrew Holt has received honoraria from both Gilead Sciences and Bristol-Myers Squibb.
Lim and Holt
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Global migration patterns have changed the demographics of many UK cities and this has prompted calls for the implementation of a universal screening and vaccination strategy to identify individuals at risk of chronic viral hepatitis.4 In central Birmingham, for instance, almost 1% of the population is hepatitis B surface antigen-positive (HBsAg+);5 in inner-city areas, up to one in 20 first-generation immigrants have serological evidence of chronic viral hepatitis. It can no longer be assumed, therefore, that chronic viral hepatitis is a lowprevalence disease in the UK, and hospitals, particularly those in large urban areas with high ethnic diversity, should routinely screen patients for the presence of viral hepatitis before these undergo chemotherapy or immunomodulatory therapies. A crucial determinant of hepatitis B virus reactivation is the patient’s serological profile Immunosuppressive and/or chemotherapeutic agents Reactivation of HBV has been reported in 20–50% of hepatitis B carriers taking immunosuppressive or chemotherapeutic agents. As these agents become more frequently used, the risk of HBV reactivation increases. Conventional chemotherapeutic agents (such as methotrexate, doxorubicin and cisplatin), which act by directly killing cancerous cells (cytotoxicity), are associated with less immunoparesis and a lower risk of HBV reactivation as monotherapies. However, when used in combination with corticosteroids, the risk of reactivation increases significantly,6 both because of the potent immunosuppressive effect and the direct stimulation of viral replication via glucocorticoid-responsive elements in the HBV genome.7
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Monoclonal antibodies such as rituximab and alemtuzumab are associated with higher risks of HBV reactivation than conventional chemotherapeutic agents. They target CD20 and CD52 antigens on B-cells (but not mature plasma cells) and mature lymphocytes, respectively, and bind to the relevant receptor to trigger immune-mediated deletion of cells expressing the antigen. It is important to note that the effects of these agents are extremely long-lasting, often bearing measurable effects on the immune system’s constitution for many months and, potentially, years.8 Impaired humoral and adaptive immune responses and Bcell depletion allow HBV to escape immune control and replicate. Rituximab is commonly used alone to treat inflammatory and autoimmune disease, or in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone) in the treatment of lymphoma, chronic lymphocytic leukaemia (CLL) and autoimmune conditions; alemtuzumab is more often used in patients with CLL and multiple sclerosis or to combat severe organ rejection. Type of malignancy It has been suggested that the type of malignancy may influence the likelihood of HBV reactivation. Patients with lymphoma or those receiving chemotherapy before haematopoietic stem cell transplantation appear to be at greatest risk, with viral flares reported in up to 50% of HBsAg+ individuals and an associated mortality of 4%.9-11 The increased risk may be explained by the need for intensive chemotherapy in these conditions, as well as the immunoparesis imparted by the disease itself. By contrast, solid organ
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tumours are associated with lower rates of HBV reactivation (14–21%); however, the risk is still reported in up to 40–50% of patients with breast cancer12 and 50–90% of renal transplant recipients.13 Serology
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A crucial determinant of HBV reactivation is the patient’s serological profile at the time of chemotherapy. The highest risk is in patients who are HBsAg+, followed by those with occult infection (that is, who are hepatitis B surface antigen-negative [HBsAg−] but hepatitis B core antibody-positive [HBcAb+]).14 Patients with true occult HBV infection (that is, who are HBsAg−, HBcAb+ and have HBV DNA below the level of detection) are considered to have the lowest likelihood of reactivation (approximately 2.7%) following rituximabcontaining chemotherapy for lymphoma,15 although recent data have suggested that this might be an underestimate.16 Screening and treatment strategies HBsAg and HBcAb testing should be performed in all patients before initiating chemotherapy or immunosuppressive therapy, particularly if rituximab is used, either alone or in combination with steroids. Screening all patients for HBsAg has been shown to be more cost-effective than screening only high-risk patients, even in low prevalence areas.17 Those who are HBsAg+ should have their HBV DNA levels quantitated by polymerase chain reaction (PCR) and receive HBV prophylaxis regardless of the levels; the HBV DNA level will guide the duration of prophylaxis in these circumstances. There is no consensus regarding how to manage patients with negative HBsAg but positive HBcAb.
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As a rule of thumb, patients with detectable viral DNA are at greater risk of seroconversion and/or reactivation and should be treated as HBsAg+ patients. The management of patients with undetectable HBV DNA is more controversial. The general consensus is to offer threemonthly follow-up with serological testing and initiation of antiviral prophylaxis upon confirmation of HBV reactivation;18 however, the cost of doing this is not inconsiderable, and it could be argued that the benefits of ensuring that all at-risk patients are treated outweigh the risks linked with unnecessary treatment. A more pragmatic approach in centres where specialist advice is limited would be to offer lamivudine prophylaxis to all patients who are HbcAb+ and HBsAg−.14 Interim data from a prospective single-centre study reported HBV reactivation in 15 out of 62 patients (24.2%) who were HBsAg−, HBcAb+ and had undetectable HBV DNA levels, and who were undergoing rituximab-based chemotherapy for haematological malignancy.16 The authors of that study noted that most reactivation occurred within the first six months of chemotherapy and that hepatitis B surface antibody (HBsAb) negativity at baseline predicted reactivation. Notwithstanding this, it is recognised that the presence of HBsAb does not always offer complete protection from reactivation in HBcAb+ individuals19 and caution is advised in these patients. While a drop in HBsAb titre can identify those at risk of HBsAg seroconversion and subsequent viral reactivation, this approach is only applicable to HBsAb-positive (HBsAb+) patients.16 The absence of HBsAg (and the presence of HBsAb) Viral Hepat Pract. Author manuscript; available in PMC 2015 April 16.
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does not guarantee that HBV DNA is absent, just as the presence of low levels of HBsAb does not guarantee safe immunity.
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The findings from these studies may alter our approach to the management of patients with resolved HBV infection, but more studies are required to validate this, and simple protocols are recommended to avoid confusion or potentially harmful delays in treatment. Some authorities recommend initiating a vaccination regimen in HBcAb+ and HBsAg/Ab− patients, but the success of vaccination in lymphoid or myeloid malignancy is often disappointing due to the impaired humoral immune response,20 and a ‘watch and wait’ strategy may be more effective in those with negative HBV DNA and normal liver function. Types and duration of treatment While there are five oral agents approved for the treatment of HBV infection – namely lamivudine, adefovir, entecavir, tenofovir and telbivudine – most experience with preemptive antiviral therapy has been with lamivudine. One randomised trial showed that the incidence of HBV reactivation in HBsAg+ patients with lymphoma who received lamivudine prophylaxis was less than 30%, compared with 50–65% in those who did not receive prophylaxis.21 There is now an established consensus that preventive therapy is more effective than reactive antiviral therapy after the flare has occurred. Only three HBsAg + patients need to be treated with lamivudine to prevent a single reactivation, which is a powerful argument in favour of prophylaxis.22 Moreover, although the cumulative rate of drug resistance after one year of lamivudine monotherapy is 24%,23 lamivudine may be sufficient for the majority of patients with low levels of HBV DNA (2,000 IU/ ml), or evidence of more advanced liver disease, it may be wise to continue therapy over the patient’s lifetime with an antiviral agent possessing a high genetic barrier to resistance. Those patients in whom antivirals are stopped should have liver function and HBV DNA levels monitored for six to 12 months thereafter to identify late reactivations of viral activity. Figure 1 shows a treatment algorithm summarising how to manage HBV reactivation in patients due to undergo chemotherapy.
HCV reactivation Risk of HCV reactivation Like HBV infection, HCV infection is also prevalent in patients with haematological malignancy. Studies have shown that HCV ribonucleic acid (RNA) can persist at very low levels in the serum and peripheral lymphoid cells, and that an intermediate replicative form of the HCV genome can persist in peripheral blood mononuclear cells for many years after apparently complete resolution of chronic hepatitis C, whether it is spontaneous or induced by antiviral therapy.28 The risk of HCV reactivation in cancer patients is thought to be approximately 10%.29 There are limited data on the course of the disease following chemotherapy, but HCV reactivation is generally associated with a lower mortality and morbidity than HBV reactivation, which might be explained by differences in the immune response to HCV antigens.30
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Rituximab is increasingly used to treat HCV-associated cryoglobulinaemic vasculitis, but, despite the elevation of HCV RNA levels observed in some patients, none have developed significant liver toxicity. However, HCV reactivation has significant clinical implications, as chemotherapy may need to be discontinued once HCV reactivation is diagnosed; liver dysfunction, especially the presence of jaundice, may delay or preclude chemotherapy; and, at present, HCV therapy cannot be given concurrently with chemotherapy. The potential deleterious effects of long-term B-cell depletion on liver function in HCV-infected patients with haematological and autoimmune diseases remain unknown. Screening and treatment strategies At present, all patients should be tested for HCV antibodies before chemotherapy, and those found to be positive should undergo a qualitative HCV RNA PCR. If they are HCV RNApositive, the decision on whether to proceed with chemotherapy should be discussed with specialists and each case weighed on its own merits. Patients should be made aware that treatment may make their liver disease worse and that this might limit the types of chemotherapy available to them.
Summary The controversies about HBV screening and prophylaxis have arisen from a lack of convincing evidence in the literature. Given the relative safety profile of oral antiviral therapy and the high mortality associated with HBV reactivation, we should adopt a lower
Viral Hepat Pract. Author manuscript; available in PMC 2015 April 16.
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threshold for initiating HBV prophylaxis in immunocompromised patients. By contrast, there is currently no approved agent to prevent HCV reactivation in immunocompromised patients. Therefore, as anti-HCV therapies improve, early detection and treatment of HCV infection to eradicate the virus before immunomodulatory therapy is initiated may be helpful to prevent the complications associated with HCV reactivation during chemotherapy
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References
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1. Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology. 2006; 43:209–220. [PubMed: 16440366] 2. Department of Health. Getting Ahead of the Curve: A strategy for combating infectious diseases (including other aspects of health protection). DH; London: 2002. [last accessed 30/04/14] 3. Office for National Statistics. [last accessed 30/04/14] Migration Statistics Quarterly Report. Nov. 2012 www.ons.gov.uk/ons/dcp171778_288105.pdf 4. Williams R, Holt AP. Screening immigrants for tuberculosis – why not for HBV infection? Lancet. 2013; 381:2164–2165. [PubMed: 23791343] 5. Unpublished data. 6. Cheng AL, Hsiung CA, Su IJ, et al. Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma. Hepatology. 2003; 37:1320–1328. [PubMed: 12774010] 7. Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA. Hepatitis B virus DNA contains a glucocorticoidresponsive element. Proc Natl Acad Sci U S A. 1986; 83:1627–1631. [PubMed: 3006059] 8. Zhang X, Tao Y, Chopra M, et al. Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis. J Immunol. 2013; 191:5867–5874. [PubMed: 24198283] 9. 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; 100:182–188. [PubMed: 1983820] 10. Lau GK, He ML, Fong DY, et al. Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell transplantation. Hepatology. 2002; 36:702–709. [PubMed: 12198664] 11. Yeo W, Zee B, Zhong S, et al. Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer. 2004; 90:1306–1311. [PubMed: 15054446] 12. Dai MS, Wu PF, Shyu RY, Lu JJ, Chao TY. Hepatitis B virus reactivation in breast cancer patients undergoing cytotoxic chemotherapy and the role of preemptive lamivudine administration. Liver Int. 2004; 24:540–546. [PubMed: 15566502] 13. Hoofnagle JH. Reactivation of hepatitis B. Hepatology. 2009; 49(5 Suppl):S156–S165. [PubMed: 19399803] 14. Barclay S, Pol S, Mutimer D, et al. Erratum to ‘The management of chronic hepatitis B in the immunocompromised patient: recommendations from a single topic meeting’. J Clin Virol. 2008; 42:104–115. [PubMed: 18572428] 15. Targhetta C, Cabras MG, Mamusa AM, Mascia G, Angelucci E. Hepatitis B virus-related liver disease in isolated anti-hepatitis B-core positive lymphoma patients receiving chemo- or chemoimmune therapy. Haematologica. 2008; 93:951–952. [PubMed: 18515881] 16. Seto, WK.; Sau Yan Chan, T.; Hwang, YY., et al. Interim analysis of hepatitis B reactivation in patients with prior HBV exposure undergoing rituximab-containing chemotherapy: a prospective study; 64th Annual Meeting of the American Association for the Study of Liver Diseases; Washington, DC. 2013; Abstract 34 17. Zurawska U, Hicks LK, Woo G, et al. Hepatitis B virus screening before chemotherapy for lymphoma: a cost-effectiveness analysis. J Clin Oncol. 2012; 30:3167–3173. [PubMed: 22711851] 18. EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol. 2009; 50:227– 242. [PubMed: 19054588] Viral Hepat Pract. Author manuscript; available in PMC 2015 April 16.
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Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts
19. Hui CK, Cheung WW, Zhang HY, et al. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology. 2006; 131:59– 68. [PubMed: 16831590] 20. Weitberg AB, Weitzman SA, Watkins E, et al. Immunogenicity of hepatitis B vaccine in oncology patients receiving chemotherapy. J Clin Oncol. 1985; 3:718–722. [PubMed: 3158725] 21. 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; 47:844–853. [PubMed: 18302293] 22. Martyak LA, Taqavi E, Saab S. Lamivudine prophylaxis is effective in reducing hepatitis B reactivation and reactivation-related mortality in chemotherapy patients: a meta-analysis. Liver Int. 2008; 28:28–38. [PubMed: 17976155] 23. Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003; 125:1714–1722. [PubMed: 14724824] 24. Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006; 253:98–108. [PubMed: 16044212] 25. Isaacs JD, Greer S, Sharma S, et al. Morbidity and mortality in rheumatoid arthritis patients with prolonged and profound therapy-induced lymphopenia. Arthritis Rheum. 2001; 44:1998–2008. [PubMed: 11592360] 26. Lin PC, Poh SB, Lee MY, et al. Fatal fulminant hepatitis B after withdrawal of prophylactic lamivudine in hematopoietic stem cell transplantation patients. Int J Hematol. 2005; 81:349–351. [PubMed: 15914368] 27. Lim SG, Wait CT, Rajnakova A, Kajiji T, Guan R. Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B. Gut. 2002; 51:597–599. [PubMed: 12235087] 28. Pham TN, MacParland SA, Mulrooney PM, et al. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J Virol. 2004; 78:5867–5874. [PubMed: 15140984] 29. Mahale P, Kontoyiannis DP, Chemaly RF, et al. Acute exacerbation and reactivation of chronic hepatitis C virus infection in cancer patients. J Hepatol. 2012; 57:1177–1185. [PubMed: 22871500] 30. Fong TL, Valinluck B, Govindarajan S, et al. Short-term prednisone therapy affects aminotransferase activity and hepatitis C virus RNA levels in chronic hepatitis C. Gastroenterology. 1994; 107:196–199. [PubMed: 8020662]
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Key points
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□
Reactivation of hepatitis B virus (HBV) frequently occurs in those who take immunosuppressive or chemotherapeutic agents.
□
HBV reactivation can be effectively prevented by prophylaxis with antiviral agents, notably lamivudine.
□
HBV reactivation is associated with a high mortality, so we should adopt a lower threshold for initiating HBV prophylaxis in immunocompromised patients.
□
Reactivation of hepatitis C virus (HCV) occurs less often and is associated with a lower mortality than HBV reactivation. There is currently no approved agent to prevent it. Ideally, the virus needs to be eradicated before the start of immunomodulatory therapy.
Europe PMC Funders Author Manuscripts Viral Hepat Pract. Author manuscript; available in PMC 2015 April 16.
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Figure 1. Treatment algorithm for managing HBV reactivation in patient due to undergo chemotherapy
Viral Hepat Pract. Author manuscript; available in PMC 2015 April 16.
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Hepatitis B and C prophylaxis in patients receiving chemotherapy Reina Lim, MB ChB MRCP [MRC Clinical Research Fellow and Senior Specialist Registrar] and Liver Research Laboratory, University of Birmingham Andrew Holt, PhD FRCP [Consultant Hepatologist] Department of Hepatology and Liver Transplantation, Queen Elizabeth Hospital, Edgbaston, Birmingham
Abstract
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Reactivation of infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) is defined as increased viral replication in patients with previously low-grade chronic infection. This may occur following the use of immunomodulatory therapy, chemotherapy or in response to severe illness. Most cases of HBV reactivation are asymptomatic; however, hepatic decompensation can occur in severe cases, where HBV reactivation is associated with a mortality of up to 30%.1 Over the last decade, it has been recognised that HBV reactivation can be effectively prevented by antiviral prophylaxis. In contrast, severe flares of hepatitis in response to HCV reactivation are less commonly reported and, when they occur, are associated with a much lower mortality. This article summarises the recent advances in this area and provides guidance for the management of HBV and HCV reactivation in patients undergoing chemotherapy.
HBV reactivation Prevalence of HBV infection The risk of HBV reactivation is influenced by the local prevalence of HBV. In 2002, the Department of Health estimated the prevalence of chronic HBV infection in adults in the UK to be 0.3% of the population.2 Other estimates have shown that the pool of chronically infected individuals may be as large as 375,000. These are almost certainly underestimates, as the last decade has seen unprecedented levels of migration across the world. It is estimated that 3% of the world’s population now lives outside their country of birth, Western Europe and North America being the most common destinations. In 2011, immigration to the UK reached 593,000 individuals per annum, 170,000 of whom had been born in new Commonwealth countries, where viral hepatitis is more prevalent than in the rest of the world.3
Copyright © Hayward Medical Communications 2014. All rights reserved. Declaration of interest Both authors declare that there is no conflict of interest. Dr Andrew Holt has received honoraria from both Gilead Sciences and Bristol-Myers Squibb.
Lim and Holt
Page 2
Europe PMC Funders Author Manuscripts
Global migration patterns have changed the demographics of many UK cities and this has prompted calls for the implementation of a universal screening and vaccination strategy to identify individuals at risk of chronic viral hepatitis.4 In central Birmingham, for instance, almost 1% of the population is hepatitis B surface antigen-positive (HBsAg+);5 in inner-city areas, up to one in 20 first-generation immigrants have serological evidence of chronic viral hepatitis. It can no longer be assumed, therefore, that chronic viral hepatitis is a lowprevalence disease in the UK, and hospitals, particularly those in large urban areas with high ethnic diversity, should routinely screen patients for the presence of viral hepatitis before these undergo chemotherapy or immunomodulatory therapies. A crucial determinant of hepatitis B virus reactivation is the patient’s serological profile Immunosuppressive and/or chemotherapeutic agents Reactivation of HBV has been reported in 20–50% of hepatitis B carriers taking immunosuppressive or chemotherapeutic agents. As these agents become more frequently used, the risk of HBV reactivation increases. Conventional chemotherapeutic agents (such as methotrexate, doxorubicin and cisplatin), which act by directly killing cancerous cells (cytotoxicity), are associated with less immunoparesis and a lower risk of HBV reactivation as monotherapies. However, when used in combination with corticosteroids, the risk of reactivation increases significantly,6 both because of the potent immunosuppressive effect and the direct stimulation of viral replication via glucocorticoid-responsive elements in the HBV genome.7
Europe PMC Funders Author Manuscripts
Monoclonal antibodies such as rituximab and alemtuzumab are associated with higher risks of HBV reactivation than conventional chemotherapeutic agents. They target CD20 and CD52 antigens on B-cells (but not mature plasma cells) and mature lymphocytes, respectively, and bind to the relevant receptor to trigger immune-mediated deletion of cells expressing the antigen. It is important to note that the effects of these agents are extremely long-lasting, often bearing measurable effects on the immune system’s constitution for many months and, potentially, years.8 Impaired humoral and adaptive immune responses and Bcell depletion allow HBV to escape immune control and replicate. Rituximab is commonly used alone to treat inflammatory and autoimmune disease, or in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone) in the treatment of lymphoma, chronic lymphocytic leukaemia (CLL) and autoimmune conditions; alemtuzumab is more often used in patients with CLL and multiple sclerosis or to combat severe organ rejection. Type of malignancy It has been suggested that the type of malignancy may influence the likelihood of HBV reactivation. Patients with lymphoma or those receiving chemotherapy before haematopoietic stem cell transplantation appear to be at greatest risk, with viral flares reported in up to 50% of HBsAg+ individuals and an associated mortality of 4%.9-11 The increased risk may be explained by the need for intensive chemotherapy in these conditions, as well as the immunoparesis imparted by the disease itself. By contrast, solid organ
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tumours are associated with lower rates of HBV reactivation (14–21%); however, the risk is still reported in up to 40–50% of patients with breast cancer12 and 50–90% of renal transplant recipients.13 Serology
Europe PMC Funders Author Manuscripts
A crucial determinant of HBV reactivation is the patient’s serological profile at the time of chemotherapy. The highest risk is in patients who are HBsAg+, followed by those with occult infection (that is, who are hepatitis B surface antigen-negative [HBsAg−] but hepatitis B core antibody-positive [HBcAb+]).14 Patients with true occult HBV infection (that is, who are HBsAg−, HBcAb+ and have HBV DNA below the level of detection) are considered to have the lowest likelihood of reactivation (approximately 2.7%) following rituximabcontaining chemotherapy for lymphoma,15 although recent data have suggested that this might be an underestimate.16 Screening and treatment strategies HBsAg and HBcAb testing should be performed in all patients before initiating chemotherapy or immunosuppressive therapy, particularly if rituximab is used, either alone or in combination with steroids. Screening all patients for HBsAg has been shown to be more cost-effective than screening only high-risk patients, even in low prevalence areas.17 Those who are HBsAg+ should have their HBV DNA levels quantitated by polymerase chain reaction (PCR) and receive HBV prophylaxis regardless of the levels; the HBV DNA level will guide the duration of prophylaxis in these circumstances. There is no consensus regarding how to manage patients with negative HBsAg but positive HBcAb.
Europe PMC Funders Author Manuscripts
As a rule of thumb, patients with detectable viral DNA are at greater risk of seroconversion and/or reactivation and should be treated as HBsAg+ patients. The management of patients with undetectable HBV DNA is more controversial. The general consensus is to offer threemonthly follow-up with serological testing and initiation of antiviral prophylaxis upon confirmation of HBV reactivation;18 however, the cost of doing this is not inconsiderable, and it could be argued that the benefits of ensuring that all at-risk patients are treated outweigh the risks linked with unnecessary treatment. A more pragmatic approach in centres where specialist advice is limited would be to offer lamivudine prophylaxis to all patients who are HbcAb+ and HBsAg−.14 Interim data from a prospective single-centre study reported HBV reactivation in 15 out of 62 patients (24.2%) who were HBsAg−, HBcAb+ and had undetectable HBV DNA levels, and who were undergoing rituximab-based chemotherapy for haematological malignancy.16 The authors of that study noted that most reactivation occurred within the first six months of chemotherapy and that hepatitis B surface antibody (HBsAb) negativity at baseline predicted reactivation. Notwithstanding this, it is recognised that the presence of HBsAb does not always offer complete protection from reactivation in HBcAb+ individuals19 and caution is advised in these patients. While a drop in HBsAb titre can identify those at risk of HBsAg seroconversion and subsequent viral reactivation, this approach is only applicable to HBsAb-positive (HBsAb+) patients.16 The absence of HBsAg (and the presence of HBsAb) Viral Hepat Pract. Author manuscript; available in PMC 2015 April 16.
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does not guarantee that HBV DNA is absent, just as the presence of low levels of HBsAb does not guarantee safe immunity.
Europe PMC Funders Author Manuscripts
The findings from these studies may alter our approach to the management of patients with resolved HBV infection, but more studies are required to validate this, and simple protocols are recommended to avoid confusion or potentially harmful delays in treatment. Some authorities recommend initiating a vaccination regimen in HBcAb+ and HBsAg/Ab− patients, but the success of vaccination in lymphoid or myeloid malignancy is often disappointing due to the impaired humoral immune response,20 and a ‘watch and wait’ strategy may be more effective in those with negative HBV DNA and normal liver function. Types and duration of treatment While there are five oral agents approved for the treatment of HBV infection – namely lamivudine, adefovir, entecavir, tenofovir and telbivudine – most experience with preemptive antiviral therapy has been with lamivudine. One randomised trial showed that the incidence of HBV reactivation in HBsAg+ patients with lymphoma who received lamivudine prophylaxis was less than 30%, compared with 50–65% in those who did not receive prophylaxis.21 There is now an established consensus that preventive therapy is more effective than reactive antiviral therapy after the flare has occurred. Only three HBsAg + patients need to be treated with lamivudine to prevent a single reactivation, which is a powerful argument in favour of prophylaxis.22 Moreover, although the cumulative rate of drug resistance after one year of lamivudine monotherapy is 24%,23 lamivudine may be sufficient for the majority of patients with low levels of HBV DNA (2,000 IU/ ml), or evidence of more advanced liver disease, it may be wise to continue therapy over the patient’s lifetime with an antiviral agent possessing a high genetic barrier to resistance. Those patients in whom antivirals are stopped should have liver function and HBV DNA levels monitored for six to 12 months thereafter to identify late reactivations of viral activity. Figure 1 shows a treatment algorithm summarising how to manage HBV reactivation in patients due to undergo chemotherapy.
HCV reactivation Risk of HCV reactivation Like HBV infection, HCV infection is also prevalent in patients with haematological malignancy. Studies have shown that HCV ribonucleic acid (RNA) can persist at very low levels in the serum and peripheral lymphoid cells, and that an intermediate replicative form of the HCV genome can persist in peripheral blood mononuclear cells for many years after apparently complete resolution of chronic hepatitis C, whether it is spontaneous or induced by antiviral therapy.28 The risk of HCV reactivation in cancer patients is thought to be approximately 10%.29 There are limited data on the course of the disease following chemotherapy, but HCV reactivation is generally associated with a lower mortality and morbidity than HBV reactivation, which might be explained by differences in the immune response to HCV antigens.30
Europe PMC Funders Author Manuscripts
Rituximab is increasingly used to treat HCV-associated cryoglobulinaemic vasculitis, but, despite the elevation of HCV RNA levels observed in some patients, none have developed significant liver toxicity. However, HCV reactivation has significant clinical implications, as chemotherapy may need to be discontinued once HCV reactivation is diagnosed; liver dysfunction, especially the presence of jaundice, may delay or preclude chemotherapy; and, at present, HCV therapy cannot be given concurrently with chemotherapy. The potential deleterious effects of long-term B-cell depletion on liver function in HCV-infected patients with haematological and autoimmune diseases remain unknown. Screening and treatment strategies At present, all patients should be tested for HCV antibodies before chemotherapy, and those found to be positive should undergo a qualitative HCV RNA PCR. If they are HCV RNApositive, the decision on whether to proceed with chemotherapy should be discussed with specialists and each case weighed on its own merits. Patients should be made aware that treatment may make their liver disease worse and that this might limit the types of chemotherapy available to them.
Summary The controversies about HBV screening and prophylaxis have arisen from a lack of convincing evidence in the literature. Given the relative safety profile of oral antiviral therapy and the high mortality associated with HBV reactivation, we should adopt a lower
Viral Hepat Pract. Author manuscript; available in PMC 2015 April 16.
Lim and Holt
Page 6
threshold for initiating HBV prophylaxis in immunocompromised patients. By contrast, there is currently no approved agent to prevent HCV reactivation in immunocompromised patients. Therefore, as anti-HCV therapies improve, early detection and treatment of HCV infection to eradicate the virus before immunomodulatory therapy is initiated may be helpful to prevent the complications associated with HCV reactivation during chemotherapy
Europe PMC Funders Author Manuscripts
References
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1. Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology. 2006; 43:209–220. [PubMed: 16440366] 2. Department of Health. Getting Ahead of the Curve: A strategy for combating infectious diseases (including other aspects of health protection). DH; London: 2002. [last accessed 30/04/14] 3. Office for National Statistics. [last accessed 30/04/14] Migration Statistics Quarterly Report. Nov. 2012 www.ons.gov.uk/ons/dcp171778_288105.pdf 4. Williams R, Holt AP. Screening immigrants for tuberculosis – why not for HBV infection? Lancet. 2013; 381:2164–2165. [PubMed: 23791343] 5. Unpublished data. 6. Cheng AL, Hsiung CA, Su IJ, et al. Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma. Hepatology. 2003; 37:1320–1328. [PubMed: 12774010] 7. Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA. Hepatitis B virus DNA contains a glucocorticoidresponsive element. Proc Natl Acad Sci U S A. 1986; 83:1627–1631. [PubMed: 3006059] 8. Zhang X, Tao Y, Chopra M, et al. Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis. J Immunol. 2013; 191:5867–5874. [PubMed: 24198283] 9. 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; 100:182–188. [PubMed: 1983820] 10. Lau GK, He ML, Fong DY, et al. Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell transplantation. Hepatology. 2002; 36:702–709. [PubMed: 12198664] 11. Yeo W, Zee B, Zhong S, et al. Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer. 2004; 90:1306–1311. [PubMed: 15054446] 12. Dai MS, Wu PF, Shyu RY, Lu JJ, Chao TY. Hepatitis B virus reactivation in breast cancer patients undergoing cytotoxic chemotherapy and the role of preemptive lamivudine administration. Liver Int. 2004; 24:540–546. [PubMed: 15566502] 13. Hoofnagle JH. Reactivation of hepatitis B. Hepatology. 2009; 49(5 Suppl):S156–S165. [PubMed: 19399803] 14. Barclay S, Pol S, Mutimer D, et al. Erratum to ‘The management of chronic hepatitis B in the immunocompromised patient: recommendations from a single topic meeting’. J Clin Virol. 2008; 42:104–115. [PubMed: 18572428] 15. Targhetta C, Cabras MG, Mamusa AM, Mascia G, Angelucci E. Hepatitis B virus-related liver disease in isolated anti-hepatitis B-core positive lymphoma patients receiving chemo- or chemoimmune therapy. Haematologica. 2008; 93:951–952. [PubMed: 18515881] 16. Seto, WK.; Sau Yan Chan, T.; Hwang, YY., et al. Interim analysis of hepatitis B reactivation in patients with prior HBV exposure undergoing rituximab-containing chemotherapy: a prospective study; 64th Annual Meeting of the American Association for the Study of Liver Diseases; Washington, DC. 2013; Abstract 34 17. Zurawska U, Hicks LK, Woo G, et al. Hepatitis B virus screening before chemotherapy for lymphoma: a cost-effectiveness analysis. J Clin Oncol. 2012; 30:3167–3173. [PubMed: 22711851] 18. EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol. 2009; 50:227– 242. [PubMed: 19054588] Viral Hepat Pract. Author manuscript; available in PMC 2015 April 16.
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19. Hui CK, Cheung WW, Zhang HY, et al. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology. 2006; 131:59– 68. [PubMed: 16831590] 20. Weitberg AB, Weitzman SA, Watkins E, et al. Immunogenicity of hepatitis B vaccine in oncology patients receiving chemotherapy. J Clin Oncol. 1985; 3:718–722. [PubMed: 3158725] 21. 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; 47:844–853. [PubMed: 18302293] 22. Martyak LA, Taqavi E, Saab S. Lamivudine prophylaxis is effective in reducing hepatitis B reactivation and reactivation-related mortality in chemotherapy patients: a meta-analysis. Liver Int. 2008; 28:28–38. [PubMed: 17976155] 23. Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003; 125:1714–1722. [PubMed: 14724824] 24. Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006; 253:98–108. [PubMed: 16044212] 25. Isaacs JD, Greer S, Sharma S, et al. Morbidity and mortality in rheumatoid arthritis patients with prolonged and profound therapy-induced lymphopenia. Arthritis Rheum. 2001; 44:1998–2008. [PubMed: 11592360] 26. Lin PC, Poh SB, Lee MY, et al. Fatal fulminant hepatitis B after withdrawal of prophylactic lamivudine in hematopoietic stem cell transplantation patients. Int J Hematol. 2005; 81:349–351. [PubMed: 15914368] 27. Lim SG, Wait CT, Rajnakova A, Kajiji T, Guan R. Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B. Gut. 2002; 51:597–599. [PubMed: 12235087] 28. Pham TN, MacParland SA, Mulrooney PM, et al. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J Virol. 2004; 78:5867–5874. [PubMed: 15140984] 29. Mahale P, Kontoyiannis DP, Chemaly RF, et al. Acute exacerbation and reactivation of chronic hepatitis C virus infection in cancer patients. J Hepatol. 2012; 57:1177–1185. [PubMed: 22871500] 30. Fong TL, Valinluck B, Govindarajan S, et al. Short-term prednisone therapy affects aminotransferase activity and hepatitis C virus RNA levels in chronic hepatitis C. Gastroenterology. 1994; 107:196–199. [PubMed: 8020662]
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Key points
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Reactivation of hepatitis B virus (HBV) frequently occurs in those who take immunosuppressive or chemotherapeutic agents.
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HBV reactivation can be effectively prevented by prophylaxis with antiviral agents, notably lamivudine.
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HBV reactivation is associated with a high mortality, so we should adopt a lower threshold for initiating HBV prophylaxis in immunocompromised patients.
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Reactivation of hepatitis C virus (HCV) occurs less often and is associated with a lower mortality than HBV reactivation. There is currently no approved agent to prevent it. Ideally, the virus needs to be eradicated before the start of immunomodulatory therapy.
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Figure 1. Treatment algorithm for managing HBV reactivation in patient due to undergo chemotherapy
Viral Hepat Pract. Author manuscript; available in PMC 2015 April 16.
