1. Please check and comment entries here.
Table of Contents

    Topic review

    Hepatitis B reactivation

    Subjects: Virology
    View times: 19
    Submitted by: Chin-Mu Hsu

    Definition

    Hepatitis B reactivation is a common complication in lymphoma patients under immunosuppressive treatment with potentially serious and life-threating consequences. 

    1. Introduction

    Hepatitis B virus (HBV) is an enveloped DNA virus that can cause a potentially life- threatening liver disease, such as liver failure and/or hepatocellular carcinoma. Although HBV vaccination and effective drugs for suppression of HBV have been widely applied in world, HBV infection is still a global health problem. Hepatitis B reactivation mostly occurs in the context of an immunosuppressed status and has been commonly reported in cancer patients receiving chemotherapy or target therapy. HBV reactivation will cause significant morbidity and mortality if not appropriately diagnosed and managed. Clinicians should be aware of HBV reactivation and screen for HBV before implementing an immunosuppressive regimen and keep monitoring HBV status in high-risk population.

    HBV reactivation has been an identified risk in lymphoma patients treated with cytotoxic chemotherapies (e.g., anthracyclines), high-dose corticosteroids, and anti-CD20 monoclonal antibody, rituximab. More and more novel agents, such as anti-CD30 monoclonal antibody, anti-CD52 monoclonal antibody, and small molecular inhibitors targeting Bruton tyrosine kinase (BTK), B-cell lymphoma-2 (BCL-2), phosphoinositide 3-kinase (PI3K), and even chimeric antigen receptor (CAR) T-cell immunotherapy have been used to treat malignant lymphoma in recent years. However, the risk of HBV reactivation in these novel agents is still undetermined. 

    HBV reactivation indicates the recurrence of active inflammatory disease in patients in the inactive phase of chronic hepatitis B (CHB) or those recovered from past infection. The definition of HBV reactivation varies between different guidelines, but the general principle is similar. In patients with CHB, HBsAg-positive at least 6 months, the reactivation is defined by an increase in HBV DNA level compared to baseline. In patients with resolved HBV infection, HBsAg-negative and anti-HBc-positive, reactivation is defined by the detection of HBV DNA or reappearance of HBsAg. Table 2 is the summary of definitions of HBV reactivation based on different society guidelines. A hepatitis flare is defined as ≥3-fold increase in ALT level compared to baseline and >100 U/L [1].

    Table 2. Definitions of HBV reactivation based on different society guidelines.

    Society Reactivaion of CHB Reactivation of Resolved HBV
    American Association for the Study of Liver Diseases (AASLD) 2018 guideline [1] Any of the following:
    • Unavailable DNA baseline: ≥10,000 IU/mL
    • Available DNA baseline, previously undetectable: ≥1000 IU/mL
    • Available DNA baseline, previously detectable: ≥100-fold increase
    Any of the following:
    • Development of detectable DNA
    • Reappearance of HBsAg (also known as reverse seroconversion)
    American Gastroenterological Association (AGA) 2015 guideline [2]
    • Unavailable DNA baseline: not explicitly defined
    • Available DNA baseline, previously undetectable: de novo detectable DNA
    • Available DNA baseline, previously detectable: ≥10-fold increase
    • Reverse seroconversion to HBsAg-positive status
    The Asian Pacific Association for the Study of the Liver (APASL) 2016 guideline [3]
    • Unavailable DNA baseline: ≥20,000 IU/mL
    • Available DNA baseline, previously undetectable: de novo detectable HBV DNA to a level of 100 IU/mL
    • Available DNA baseline, previously detectable: ≥2 log increase from baseline levels
    • Not clearly defined
    European Association for the Study of the Liver (EASL) 2017 guideline [4]
    • No clearly defined
    • Not clearly defined
    Korean Association for the Study of the Liver (KASL) 2019 guideline [5]
    • An increase in serum HBV DNA by more than 100 times the baseline level
    • Seroconversion of HBsAg-negative to positive
    • Detection of serum HBV DNA from none to positive
    American Society of Clinical Oncology (ASCO) 2020 update [6]
    • The same as the AASLD guidelines
    • The same as the AASLD guidelines

    2. Risk Factors for HBV Reactivation

    2.1. Host Factors

    In previous studies, older age and male sex have been identified as risk factors for HBV reactivation [7][8][9][10]. In addition, a survey of 1692 patients with hematologic malignancy found that diabetes mellitus, liver cirrhosis, and hepatocellular carcinoma were independent risk factors of HBV reactivation [11]. All these findings indicate that the immunocompromised host is a significant risk factor for HBV reactivation.

    2.2. Virological Factors

    HBV infection causes covalently closed circular DNA (cccDNA) in hepatocytes, regardless of HBsAg or HBV DNA status. The cccDNA is quite stable in infected cells and can persist in a latent state. The persistence of cccDNA is the key driver for HBV reactivation [12]. HBsAg positivity, HBeAg positivity and the high HBV DNA levels before immunosuppressive therapy have also been known risk factors for HBV reactivation [13][14][15][16]. The risk of HBV reactivation is five- to eight-fold higher in HBsAg patients [16]. High HBV viral load prior to cytotoxic chemotherapy is a prominently predictive factor for HBV reactivation [15]. In resolved HBV infection patients, many studies showed that negative baseline anti-HBs carried a higher risk of HBV reactivation [9][10][17][18][19][20].

    2.3. Immunosuppressive Regimens

    2.3.1. Corticosteroids

    Corticosteroids are used in the treatment of lymphoma for a long time. Firstly, corticosteroids upregulate the HBV glucocorticoid responsive element (a transcriptional regulatory element) and promote viral replications. Secondly, they cause a direct suppressive effect on cytotoxic T cells which is involved in HBV control [21]. The above two mechanisms explain the susceptibility to HBV reactivation in patients who receive corticosteroids. The immunosuppressive effect of steroids is dose and duration dependent.

    2.3.2. Anti-CD20 Monoclonal Antibodies

    Rituximab, an anti-CD20 monoclonal antibody widely used in lymphoma treatment, has been well known a vital risk factor for HBV reactivation. Several studies have reported the risk of HBV reactivation in rituximab treatment. Both HBsAg-positive and resolved HBV infection patients who receive these agents are susceptible to HBV reactivation [10][17][22][23][24][25][26][27].

    2.3.3. Other Monoclonal Antibodies

    Alemtuzumab, a monoclonal antibody against CD52, used to treat refractory CLL or as a conditioning regimen in hematopoietic stem cell transplantation, has been reported to induce HBV reactivation and related hepatitis. Two CLL subjects with occult HBV infection developing a virological and biochemical flare of hepatitis B following immunotherapy with alemtuzumab were reported [28]. Brentuximab vedotin, an antibody–drug conjugate medication, which targets tumor cells expressing CD30, is used for T cell lymphoma and relapsed or refractory Hodgkin lymphoma. A case of HBV reactivation was reported from China.

    2.3.4. Other Novel Agents

    Ibrutinib is used to treat mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, marginal zone lymphoma and chronic graft-versus-host disease in allo-hematopoietic stem cell transplantation. It inhibits (Bruton’s tyrosine kinase (BTK) and thereby interrupts the B-cell receptor signaling pathway which regulates B cell proliferation and activation [29]. Idelalisib, a PI3K inhibitor, is approved for indolent lymphoma treatment. A total of 13–25% of patients reported grade 3 or higher elevations of serum aminotransferase levels and most cases are asymptomatic and resolved following dose reduction [30][31]. Bortezomib, a proteasome inhibitor, is used for treatment of multiple myeloma (MM) and mantle cell lymphoma, HBV reactivation occurred in six HBsAg-positive patients and two HBsAg -negative patients, including six who received autologous stem cell transplant (ASCT).  Venetoclax is a potent inhibitor of the antiapoptotic BCL-2 protein and is used for CLL and acute myeloid leukemia treatment,  it may have a potential risk of HBV reactivation.

    2.3.5. Chimeric Antigen Receptor (CAR) T-Cell Immunotherapy

    CAR T cell immunotherapy has recently been found to be a novel and effective treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) [32][33][34][35].

    3. Summary

    HBV reactivation exerts a negative impact on the clinical outcomes in patients with malignant lymphoma. All patients should be screened for HBV status prior immunosuppressive therapy. The risk of HBV reactivation should be assessed by virological markers and immunosuppressive regimens individually. Given the efficacy of NAs against HBV, prophylactic therapy is a more effective strategy to manage HBV reactivation. Prophylaxis is recommended for all HBsAg-positive patients and HBsAg-negative, anti-HBc-positive patients with detectable HBV DNA or high risk for HBV reactivation. Liver function, HBsAg, and HBV DNA should continue to be monitored for at least 12 months after the cessation of prophylaxis. Several novel agents for lymphoma treatment have emerged in recent years. However, only few HBV reactivation cases were reported. The real incidence and risk of HBV reactivation in these novel agents is still unclear to date. It is imperative to conduct larger studies to clarify the risk of HBV reactivation and provide a comprehensive guideline to prevent HBV reactivation during novel agent treatment.

    The entry is from 10.3390/jpm11040267

    References

    1. Terrault, N.A.; Lok, A.S.; McMahon, B.J.; Chang, K.-M.; Hwang, J.P.; Jonas, M.M.; Brown, R.S., Jr.; Bzowej, N.H.; Wong, J.B. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018, 67, 1560–1599.
    2. Perrillo, R.P.; Gish, R.; Falck-Ytter, Y.T. American Gastroenterological Association Institute Technical Review on Prevention and Treatment of Hepatitis B Virus Reactivation During Immunosuppressive Drug Therapy. Gastroenterology 2015, 148, 221–244.e3.
    3. Sarin, S.K.; Kumar, M.P.; Lau, G.K.; Abbas, Z.; Chan, H.L.Y.; Chen, C.J.; Chen, D.S.; Chen, H.L.; Chien, R.N.; Dokmeci, A.; et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: A 2015 update. Hepatol. Int. 2016, 10, 1–98.
    4. European Association for the Study of the Liver. EASL 2017. Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol. 2017, 67, 370–398.
    5. Korean Association for the Study of the Liver. KASL clinical practice guidelines for management of chronic hepatitis B. Clin. Mol. Hepatol. 2019, 25, 93–159.
    6. Hwang, J.P.; Feld, J.J.; Hammond, S.P.; Wang, S.H.; Alston-Johnson, D.E.; Cryer, D.R.; Hershman, D.L.; Loehrer, A.P.; Sabichi, A.L.; Symington, B.E.; et al. Hepatitis B Virus Screening and Management for Patients with Cancer Prior to Therapy: ASCO Provisional Clinical Opinion Update. J. Clin. Oncol. 2020, 38, 3698–3715.
    7. Bo, W.; Ghulam, M.; Kosh, A. Reactivation of hepatitis B virus infection in patients with hematologic disorders. Haematologica 2019, 104, 435–443.
    8. Lok, A.S.; Liang, R.H.; Chiu, E.K.; Wong, K.-L.; Chan, T.-K.; Todd, D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Gastroenterology 1991, 100, 182–188.
    9. Koo, Y.X.; Tay, M.; Teh, Y.E.; Teng, D.; Tan, D.S.W.; Tan, I.B.H.; Tai, D.W.M.; Quek, R.; Tao, M.; Lim, S.T. 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, 1219–1223.
    10. Yeo, W.; Chan, T.C.; Leung, N.W.Y.; Lam, W.Y.; Mo, F.K.F.; Chu, M.T.; Chan, H.L.Y.; Hui, E.P.; Lei, K.I.K.; Mok, T.S.K.; 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, 605–611.
    11. Chen, C.-Y.; Tien, F.-M.; Cheng, A.; Huang, S.-Y.; Chou, W.-C.; Yao, M.; Tang, J.-L.; Tien, H.-F.; Sheng, W.-H. Hepatitis B reactivation among 1962 patients with hematological malignancy in Taiwan. BMC Gastroenterol. 2018, 18, 6.
    12. Loomba, R.; Liang, T.J. Hepatitis B Reactivation Associated with Immune Suppressive and Biological Modifier Therapies: Current Concepts, Management Strategies, and Future Directions. Gastroenterology 2017, 152, 1297–1309.
    13. Yeo, W.; Chan, P.K.; Zhong, S.; Ho, W.M.; Steinberg, J.L.; Tam, J.S.; Hui, P.; Leung, N.W.; Zee, B.; Johnson, P.J. 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. 2000, 62, 299–307.
    14. Lau, G.K.K.; Leung, Y.-H.; Fong, D.Y.T.; Au, W.-Y.; Kwong, Y.-L.; Lie, A.; Hou, J.-L.; Wen, Y.-M.; Nanj, A.; Liang, R. 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 2002, 99, 2324–2330.
    15. Yeo, W.; Zee, B.; Zhong, S.; Chan, P.K.S.; Wong, W.-L.; Ho, W.M.; Lam, K.C.; Johnson, P.J. 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.
    16. Shibolet, O.; Shouval, D. Immunosuppression and HBV Reactivation. Semin. Liver Dis. 2013, 33, 167–177.
    17. Seto, W.-K.; Chan, T.S.; Hwang, Y.-Y.; Wong, D.K.-H.; Man-Fung, Y.; Liu, K.S.-H.; Gill, H.; Yok-Lam, K.; Lie, A.K.; Lai, C.-L.; et al. Hepatitis B Reactivation in Patients with Previous Hepatitis B Virus Exposure Undergoing Rituximab-Containing Chemotherapy for Lymphoma: A Prospective Study. J. Clin. Oncol. 2014, 32, 3736–3743.
    18. Cho, Y.; Yu, S.J.; Cho, E.J.; Lee, J.H.; Kim, T.M.; Heo, D.S.; Kim, Y.J.; Yoon, J.H. High titers of anti-HBs prevent rituximab-related viral reactivation in resolved hepatitis B patient with non-Hodgkin’s lymphoma. J. Med. Virol. 2016, 88, 1010–1017.
    19. Paul, S.; Dickstein, A.; Saxena, A.; Terrin, N.; Viveiros, K.; Balk, E.M.; Wong, J.B. Role of surface antibody in hepatitis B reactivation in patients with resolved infection and hematologic malignancy: A meta-analysis. Hepatology 2017, 66, 379–388.
    20. Matsubara, T.; Nishida, T.; Shimoda, A.; Shimakoshi, H.; Amano, T.; Sugimoto, A.; Takahashi, K.; Mukai, K.; Yamamoto, M.; Hayashi, S.; et al. The combination of anti-HBc and anti-HBs levels is a useful predictor of the development of chemotherapy-induced reactivation in lymphoma patients with resolved HBV infection. Oncol. Lett. 2017, 14, 6543–6552.
    21. Tur-Kaspa, R.; Shaul, Y.; Moore, D.D.; Burk, R.D.; Okret, S.; Poellinger, L.; Shafritz, D.A. The glucocorticoid receptor recognizes a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer. Virology 1988, 167, 630–633.
    22. Pei, S.N.; Chen, C.H.; Lee, C.M.; Wang, M.C.; Ma, M.C.; Hu, T.H.; Kuo, C.Y. Reactivation of hepatitis B virus following rituximab-based regimens: A serious complication in both HBsAg-positive and HBsAg-negative patients. Ann. Hematol. 2010, 89, 255–262.
    23. Evens, A.M.; Jovanovic, B.D.; Su, Y.-C.; Raisch, D.W.; Ganger, D.; Belknap, S.M.; Dai, M.-S.; Chiu, B.-C.C.; Fintel, B.; Cheng, Y.; et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: Meta-analysis and examination of FDA safety reports. Ann. Oncol. 2011, 22, 1170–1180.
    24. Oh, M.J.; Lee, H.J. 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, 51–59.
    25. Gutiérrez García, M.L.; Alonso Lopez, S.; Martín Rios, M.D.; Sanmartin Fenollera, P.; Agudo Fernandez, S.; Fernández Rodriguez, C.M. Hepatitis B virus reactivation in rituximab-treated patients: Incidence and risk factors. Gastroenterol. Hepatol. 2015, 38, 1–6.
    26. Guo, Y.-F.; Pan, J.-X.; Zhuang, W.-H. Concurrent and reactivation of hepatitis B virus infection in diffuse large B-cell lymphoma: Risk factors and survival outcome. Infect. Agents Cancer 2018, 13, 40.
    27. Tsai, Y.-F.; Yang, C.-I.; Du, J.-S.; Lin, M.-H.; Tang, S.-H.; Wang, H.-C.; Cho, S.-F.; Liu, Y.-C.; Su, Y.-C.; Dai, C.-Y.; et al. Rituximab increases the risk of hepatitis B virus reactivation in non-Hodgkin lymphoma patients who are hepatitis B surface antigen-positive or have resolved hepatitis B virus infection in a real-world setting: A retrospective study. PeerJ 2019, 7, e7481.
    28. Iannitto, E.; Minardi, V.; Calvaruso, G.; Mulè, A.; Ammatuna, E.; Trapani, R.D.; Ferraro, D.; Abbadessa, V.; Craxi, A.; Stefano, R.D. Hepatitis B virus reactivation and alemtuzumab therapy. Eur. J. Haematol. 2005, 74, 254–258.
    29. Pan, Z.; Scheerens, H.; Li, S.-J.; Schultz, B.E.; Sprengeler, P.A.; Burrill, L.C.; Mendonca, R.V.; Sweeney, M.D.; Scott, K.C.K.; Grothaus, P.G.; et al. Discovery of Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase. ChemMedChem 2006, 2, 58–61.
    30. Gopal, A.K.; Kahl, B.S.; De Vos, S.; Wagner-Johnston, N.D.; Schuster, S.J.; Jurczak, W.J.; Flinn, I.W.; Flowers, C.R.; Martin, P.; Viardot, A.; et al. PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma. N. Engl. J. Med. 2014, 370, 1008–1018.
    31. Flinn, I.W.; Kahl, B.S.; Leonard, J.P.; Furman, R.R.; Brown, J.R.; Byrd, J.C.; Wagner-Johnston, N.D.; Coutre, S.E.; Benson, D.M.; Peterman, S.; et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood 2014, 123, 3406–3413.
    32. Neelapu, S.S.; Locke, F.L.; Bartlett, N.L.; Lekakis, L.J.; Miklos, D.B.; Jacobson, C.A.; Braunschweig, I.; Oluwole, O.O.; Siddiqi, T.; Lin, Y.; et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N. Engl. J. Med. 2017, 377, 2531–2544.
    33. Chow, V.A.; Shadman, M.; Gopal, A.K. Translating anti-CD19 CAR T-cell therapy into clinical practice for relapsed/refractory diffuse large B-cell lymphoma. Blood 2018, 132, 777–781.
    34. Roberts, Z.J.; Better, M.; Bot, A.; Roberts, M.R.; Ribas, A. Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL. Leuk. Lymphoma 2017, 59, 1785–1796.
    35. Stirrups, R. CAR T-cell therapy in refractory large B-cell lymphoma. Lancet Oncol. 2018, 19, e19.
    More