Hepatitis B reactivation. Geoffrey Dusheiko UCL Institute for Liver and Digestive Health Royal Free Hospital London, UK

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1 Hepatitis B reactivation Geoffrey Dusheiko UCL Institute for Liver and Digestive Health Royal Free Hospital London, UK

2 HBV reactivation Defined as abrupt rise in HBV replication (> 1 log) Followed by lab signs of hepatocellular injury Typically in asymptomatic hepatitis B carrier: HBsAg positive Also in occult hepatitis B: HBsAg negative anti-hbc positive anti-hbs negative HBsAg negative anti-hbc positive, anti-hbs positive HBsAg seroreversion Clinical presentation variable Sanchez MJ, et al. J Hepatol 2009;51: ;Shouval D et al Sem Liv Dis 2013: 33:

3 HBV persistence after recovery from acute hepatitis B despite active maintenance of a cytotoxic T-Cell response CTL* responsiveness and HBV DNA following acute viral hepatitis Subject HBV DNA (PCR) Total CRI CRI-P peptides Years after acute hepatitis Serum PBMC SUM neg neg neg neg neg neg neg neg neg neg neg neg neg pos neg pos neg pos neg pos neg pos pos pos pos neg pos pos pos pos pos pos pos pos * CTL: cytotoxic T Lymphocytes, CRI-P: CTL response index for peptide Rehermann B, et al. Nat Med 1996;2:

4 Hepatitis B virus reactivation Variable time interval to Hepatic Flare Hepatic Failure Immune suppression Chronic Hepatitis HBV DNA ALT Acute Hepatitis TIME Adapted from Lau GKK, et al. Crit Rev Oncol Hematol 1999;31:71-76.

5 Therapies associated with HBV reactivation Chemotherapy for cancer, haematological malignancies1, 2, 3 Especially rituximab, corticosteroids Autoimmune diseases, e.g. rheumatoid arthritis, inflammatory bowel disease, psoariasis, 1, 2 Corticosteroids, anti-tnf antibodies, methotrexate Anti-TNF agents Infliximab, etanercept, adalimumab Transplantation 4 Solid organ (renal and liver) and bone marrow anthracyclines 1. Sorrell MF, et al. Ann Intern Med 2009;150: Lok ASF, McMahon BJ. Hepatology 2009;50(3): Yeo W, & Johnson PJ. Hepatology 2006;43: Sanchez MJ, et al. J Hepatol 2009;51:

6 Incidence of HBV reactivation Systematic review of patients undergoing chemotherapy 485 HBsAg positive patients without antiviral prophylaxis Incidence of HBV reactivation: 24 87% Reports on mortality: 5-71% Loomba R, et al. Ann Intern Med 2008;148: ; Torres et al Nat Rev Clin Oncol 2012: ; Kawsar et al Clin Adv Hem Onc 10: , 2012.

7 Risk factors Type of chemotherapeutic, cytotoxic, immunomodulatory regimen Highest risk Lymphoma treated anthracyclines and monoclonal antibodies Rituximab (CD20) or alemtuzumab (CD52), usually with corticosteroids (CHOP) May occur in patient with solid tumours Organ transplantation Including recipient anti-hbc positive graft Autoimmune disease Rheumatologic and dermatological disease Inflammatory bowel disease

8 HBV reactivation after chemotherapy for lymphoma: meta-analysis Outcome Probability Sensitivity analysis Reactivation without HBV prophylaxis 51% 27 85% Reactivation with lamivudine prophylaxis 9% 0 18% HBV-related mortality without HBV prophylaxis 6% 0 17% HBV-related mortality with lamivudine prophylaxis 2% 0 8% Ziakas PD, et al. Haematologica 2009;94:

9 Predictive factors for HBV reactivation Patient Virus Therapy Male HBsAg+ve High steroids Young HBeAg+ve Monoclonal antibodies Immune-suppressed Genotype? Not vaccinated DNA-HBV >2000 IU/mL Pre-core mutation CHOP Chemotherapy/ R-CHOP HBsAg positive, lymphoma or stem cell or bone marrow transplantation highest risk Anti-HBc positive, anti-hbs positive (>10 iu/ml), HBV DNA negative lowest risk CHOP Chemotherapy: cyclophosphamide, doxorubicin, vincristine and prednisone R-CHOP Chemotherapy: rituximab + CHOP Yeo W, et al. J Clin Oncol 2009;27:

10 Rituximab-associated HBV reactivation in lymphoproliferative diseases: Meta-analysis and examination of FDA safety reports Humanised chimeric MoAb Effective against B cell tumours; sometimes used in idiopathic thrombocytopenic purpura Strong association with HBV reactivation Among anti-hbc positive: ritixumab-based therapy showed a five fold increased risk of HBV-reactivation compared with non ritixumab treated patients (odds ratio: 5.73, 95% confidence interval: ; p=0.0009) Timing: From last rituximab to reactivation: 3 months (0 12), but 29% occurred >6 months after last rituximab Evens AM, et al. Ann Oncol 2011; 22:

11 Asia Lymphoma Study Group Retrospective analysis (n = 340) vs prospective monitoring (single centre n = 127) Rituximab containing chemotherapy Reactivation in 27% HBsAg positive patients 22% those with prophylaxis and 59% those who did not (retrospective analysis) Lamivudine most commonly used: 20% of HBsAg positive break through reactivation Cross sectional analysis Entecavir 6.3% vs lamivudine (39%) Kim et al European Journal Cancer in press 2013

12 Early vs deferred preemptive treatment (Rx) 100 HBV reactivation in patients with lymphoma Survival free from hepatitis B virological reactivation (%) Group 1 Reactivation rate P=0.001 by log rank test Early Rx (1 week before chemo) 0% Group 2 Deferred Rx (after HBV reactivation) 53% Weeks Lau GKK, et al. Gastroenterology 2003;125:

13 Hepatitis B virus (HBV) reactivation and hepatitis B surface antigen (HBsAg) seroreversion entecavir (ETV) prophylactic and control groups. Huang Y et al. JCO 2013;31:

14 Entecavir vs Lamivudine for chemotherapy prophylaxis N = 40 LAM and ETV equally efficacious in patients with resolved HBV infection If HBV DNA undetectable ETV preferred in patients with detectable HBV DNA Chen et al Liver Int. 2013: 33:

15 Anti-rheumatic drugs and hepatitis B Treatment with: and odds ratio corticosteroids [ROR 2.3 (95 % confidence interval )], methotrexate [4.9 ( )], rituximab [7.2 ( )], tacrolimus [4.2 ( )], Adalimumab had a lower ROR [0.2 ( )] Other anti-tnf agents: leflunomide? Oshima Y Mod Rheumatol Jul;23(4): ; Cobeta Garcia Reumatol Clin May-Jun;7(3):200-2 Reviewed: Shouval et al Sem Liver Disese 33:

16 Anti-TNF treatment or prednisone treatment TNF-a inhibitors potential immunologic interactions with hepatitis B virus. High concentrations of TNF-α are capable of destroying virally infected hepatocytes. TNF-α also reduces HBV transcription- impairs virus production Non cytolytic killing Polymorphisms in the TNF-α gene exist, and certain variants have been linked to HBV persistence in humans HBV genome contains a corticosteroid-response receptor on hepatitis B core protein upregulates HBV replication Increase in HBV DNA levels during prednisone therapy Romero R, Lavine JE. Hepatol 1996; 23: Guidotti LG, Ishikawa T, Hobbs MV, et al. Immunity 1996; 4: Ganem D, Prince A. N Engl J Med 2004; 350: ) Hohler T, Kruger A, Gerken G, et al. Clin Exp Immunol 1998; 111:

17 Prevention of recurrent hepatitis B after liver transplantation HBIg and lamivudine is (was) the standard prophylaxis 1 Shorter courses and lower doses of HBIg and other forms of prophylaxis, including tenofovir ± emtricitabine or entecavir monotherapy, are being studied 1 3 Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use in HBV 1. EASL. J Hepatol 2009; 50: Temperman L, et al. EASL 2011; Poster #574, 3. Fung J, et al. Gastroenterology 2011; 141:

18 New nucleosides Tenofovir and entecavir More potent and less resistant Can HBIG be discontinued? Might fully replace HBIG as prophylaxis and treatment regimen? (Jimenez-Perez, 2010a: )

19 HBV DNA level pre-transplant predicts risk of HBV recurrence 100 P = % HBV recurrence HBV DNA > 100,000 copies/ml at time of surgery (n=18) HBV DNA <100,000 copies/ml at time of surgery (n=159) 0 1,000 2,000 3,000 Days Post-LT 1. Adapted from Marzano A, et al. Liver Transplantation 2005;11:

20 Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation % 91% Cumulative rate of HBsAg seroclearance Months after liver transplantation Number of patients at risk Overall group Adapted from Fung J, et al. Gastroenterology 2011; 141:

21 Can HBIg be discontinued? In favour of discontinuation: High cost 1 The necessity of a high degree of compliance Few cases of HBV recurrence (HBsAg-ve) after 5 years of liver transplant (LT) 2 Against discontinuation: Presence of HBV DNA by PCR in serum, liver and PBMC in 45% of patients after 10 years of LT 2 HBV recurrence is a life-threatening condition 3 Reduces graft survival No proven role entecavir + tenofovir 1.Angelico M, et al. Hepatology 2002;35: Roche B, et al. Hepatology 2003;38: Sánchez-Fueyo A, et al. Hepatology 2000;31:

22 Controversy: screening prophylaxis solid tumours Centre for Disease Control and Prevention recommends pre-chemotherapy hepatitis B screening for all American Society of Clinical Oncology finds that there is insufficient evidence currently to support such a recommendation.

23 Prophylaxis for HBV reactivation: recommendations Need to increase awareness Hepatologists, haematologists, dermatologists, oncologists, rheumatologists, gastroenterologists Screening and pre-emptive treatment HBsAg positive patients receiving anti-tnf Pre emptive prophylaxis HBsAg negative: serial monitoring HIV early and uninterrupted antiviral therapy incorporated into antiretroviral regimen coinfected individuals 1. Sorrell MF, et al. Ann Intern Med 2009;150: ;.2. Lok ASF, McMahon BJ. Hepatology 2009;50: Hui CK, et al. Gut 2005;54: Lau GKK, et al. Gastroenterology 2003;125:

24 Prophylaxis for HBV reactivation: recommendations HBsAg positive patients should receive antiviral therapy for HBV prior to the initiation of any immunosuppressive therapy 1, 2 Including inactive carriers Antiviral therapy should be maintained throughout the course of treatment and for at least 6 months afterwards 1, 2 Withdrawal too soon after completion of chemotherapy can result in reactivation 3 Initiation after reactivation has occurred is not entirely satisfactory 4 1. Sorrell MF, et al. Ann Intern Med 2009;150: ;.2. Lok ASF, McMahon BJ. Hepatology 2009;50: Hui CK, et al. Gut 2005;54: Lau GKK, et al. Gastroenterology 2003;125:

25 Pre-emptive therapy prior to immunosuppression or chemotherapy HBsAg and anti HBc and anti-hbs screening HBsAg ve anti-hbc +ve Measure HBV DNA HBsAg +ve HBV Vaccination Monitoring Prophylaxis Chronic hepatitis B Inactive carrier Tenofovir Entecavir HBV DNA <2000 IU/mL: lamivudine HBV DNA >2000 IU/mL: tenofovir or entecavir