Immunosuppression and HBV Reactivation Associate Professor Joe Sasadeusz

Transcription

1 Immunosuppression and HBV Reactivation Associate Professor Joe Sasadeusz

2 Mr BR 40 yo man originally from New Caledonia PH complex, chronic perianal fistula Nov 2008 Diagnosed with MALT lymphoma in colonic polyp removed at colonoscopy Feb 2009 Initially observed with no Rx Further colonoscopy July 2009 showed progressive involvement + PET scan demonstrated multinodal involvement Commenced chemo with CVP-R in 14 th October 2010

3 Mr BR Urgent call Friday evening late Dec 2010 as noticed pre chemo screen was HBsAg+ Now completed 3 cycles chemo and due for 4 th but deferred as febrile, settled with ABs Commenced empirically on entecavir 0.5 mg/day that night Bloods : HBeAg +, HBV viral load 174,496,545 (8.242 log 10 ) IU/ml, ALT 52 U/ml, SBR 11 umol/l Review of bloods pre Rx (1/10/10): HBsAg+, ALT 28, HBV DNA 15,511 U/Ml

4 Mr BR Review 24/1/11: ALT increased to 941 U/ml with SBR 32 umol/l, INR 1.1, HBV DNA decreased to 691,443 U/ml Chemo delayed Patient asymptomatic Bloods 7/3/11: ALT 40 U/ml, HBV DNA 348 U/ml Fibroscan 7.3 KPa (c/w F1-2) Completed 2 further cycles of chemo Now in full remission with HBV VL <20 U/ml and ALT 35 U/ml

5 Background

6 Epidemiology of Hepatitis B 400 million chronically infected worldwide 2 billion with markers of prior infection Percentage chronic HBsAg carriers: Margolis et al, 1991 < 2% - Low 2-7% - Intermediate > 8% - High

7 Background 75% of CHB occur s in Southeast Asia and Western Australian prevalence in 2011 ~ 192, ,000 cases (~1%) but areas of increased prevalence Estimated only 56% diagnosed Increasing migration to Australia from endemic countries Likely to become a bigger problem locally and internationally MacLachlan ANZJ Public Health.2013; ; in press

8 Notifications of chronic hepatitis B by LGA per 100,000 persons per year, Maribyrnong

9 HBV Phases Most Oncology Patients HBV DNA ALT HBeAg Anti-HBe Immune Tolerance Immune Clearance Immune Control Immune escape Resolved HBV: HBsAg neg/anti-hbc pos/anti-hbsab pos

10 Do You Ever Really Get Rid of HBV? T cell cccdna T cell T cell Immune control not clearance Resolved HBV a misnomer still HBV DNA in liver Werle-Lapostolle B, et al. Gastroenterology. 2004;126:

11 Along Comes Immune Suppression T cell cccdna T cell HIV Steroids Chemotx T cell Immune control can be lost Immune-mediated liver damage with immune reconstitution Werle-Lapostolle B, et al. Gastroenterology. 2004;126:

12 HBV Reactivation HBeAg+ HBeAg- HBeAb+ HBeAg+ Immunotolerance Immune Clearance Immune Suppression Immune Reconstitution HBV DNA ALT Infection 5-30 Yrs Mos-Yrs Mos-Yrs Hoofnagle JH. Hepatology. 2009;49(5 suppl):s156-s165.

13 HBV Reactivation Definition Loss of HBV immune control in a patient with inactive or resolved HBV infection Abrupt reappearance or increase in viral replication with liver damage occurring during and/or following immune reconstitution Clinically Rise in HBV DNA ± return of HBeAg ALT increase (may be mild or very dramatic) Range from subclinical to severe/fatal hepatitis May progress to liver failure/death despite antiviral therapy Hoofnagle JH. Hepatology. 2009;49(5 suppl):s156-s165.

14 Imunosuppressive Interventions Reported to Cause HBV Reactivation Chemotherapy Corticoteroids Transplantation Immunomodulatory Therapy Anti B cell MABs (rituximab) Anti-TNF Roche B, et al. Liver Int. 2011;31(suppl 1):

15 HBsAg Patients (%) Reactivation in Hematologic Malignancy 100 patients with NHL undergoing CHOP; 27 HBsAg positive HBV Reactivation Jaundice 4 4 Nonfatal Liver Failure Death Lok AS, et al. Gastroenterology. 1991;100:

16 HBsAg Patients (%) Steroids Increase Risk of HBV Reactivation 50 patients with NHL who were HBsAg positive randomized to epirubicin, cyclophosphamide and etoposide (ACE) ± prednisolone (P) * HBV Reactivation 13 44* ALT > 10 x ULN 4 28* Jaundice Complete Remission Survival at 4 Yrs ACE PACE *P <.05 Cheng AL, et al. Hepatology. 2003;37: Prednisolone increased risk and severity of HBV reactivation but trend toward improved NHL outcome

17 Rate of HBV Reactivation: Solid Tumors HBsAg-positive breast cancer patients receiving chemotherapy Rate of HBV-associated acute hepatitis: 21% [1] With careful HBV DNA monitoring, up to 41% with HBV reactivation [2] HBV DNA may be undetectable by time of ALT peak Limited data on other solid tumors Of those who flare [2] : 35% chemotherapy interruption 35% premature termination of chemotherapy 1. Kim MK, et al. Korean J Intern Med. 2007;22: Yeo W, et al. J Med Virol. 2003;70:

18 Management

19 Survival free from hepatitis B virological reactivation (%) Early vs Deferred Preemptive Treatment 100 HBV reactivation in patients with lymphoma 75 P=0.001 by log rank test Group 1 Reactivation rate Early Rx (1 week before chemo) 0/15 (0%) Group 2 Deferred Rx (after HBV reactivation) 8/15 (53%) Weeks Lau GKK, et al. Gastroenterology 2003;125:

20 Lamivudine Prophylaxis Systematic Review 14 studies enrolled 275 HBsAg + ve patients with and 485 without lamivudine prophylaxis Loomba R, et al. Ann Intern Med 2008;148:

21 Choice of Antiviral Therapy and Monitoring Choice of therapy affected by HBV DNA level HBV DNA < 2000 IU/mL: any therapy can be used (including lamivudine) HBV DNA > 2000 IU/mL: entecavir or tenofovir Choice of therapy affected by duration of therapy > 12 mos: entecavir or tenofovir HBV DNA and ALT should be monitored every 3 mos EASL. J Hepatol. 2009;50: Lok AS, et al. Hepatology. 2009;50:

22 Timing of Antiviral Therapy When to start Ideally before or together with chemotherapy Do not delay start of chemotherapy When to stop If baseline HBV DNA > 2000 IU/mL: high risk of withdrawal flare, continue therapy as for chronic HBV infection If baseline HBV DNA < 2000 IU/mL, 6-12 mos after end of chemotherapy Monitor for withdrawal flares with monthly HBV DNA and ALT EASL. J Hepatol. 2009;50: Lok AS, et al. Hepatology. 2009;50:

23 Entecavir Vs Lamivudine in R-CHOP HBsAg + Normal LFTs HBV VL < 10 3 c/ml No prior antiviral therapy Huang et.al. JAMA.2104; 312 (23): case hepatic failure in LMV arm Reactivations occurred up to 19 months after initiation of chemotherapy.

24 HBV Screening

25 What Is the Optimal Screening Strategy? Screening high-risk individuals requires recognition of high-risk population Screening all patients is easiest to implement HBsAg should be tested in all individuals, with follow-up HBV DNA in HBsAgpositive patients Role of anti-hbc testing less clear; recommendations from various societies mixed EASL: HBsAg and anti-hbc [1] AASLD: HBsAg and anti-hbc [2] CDC: HBsAg and anti-hbc and anti-hbs [3] ASCO: Consider HBsAg alone [4] 1. EASL. J Hepatol. 2009;50: Lok AS, et al. Hepatology. 2009;50: Weinbaum CM, et al. Hepatology. 2009:49(suppl 5):S35-S Artz AS, et al. J Clin Oncol. 2010;28:

26 Who Should Be Screened? AASLD recommends screening high-risk individuals [1] Immigrants Asia, Africa, Pacific Islands, Middle East, Eastern Europe, South/Central America, Caribbean, Aboriginal Children of immigrants Men who have sex with men HIV/HCV positive History of IDU, incarceration Hemodialysis patients Lok AS, et al. Hepatology. 2009;50:

27 Who Should Be Screened? AASLD recommends screening high-risk individuals [1] Immigrants Asia, Africa, Pacific Islands, Middle East, Eastern Europe, South/Central America, Caribbean, Aboriginal Children of immigrants Men who have sex with men HIV/HCV positive History of IDU, incarceration Hemodialysis patients 1. Lok AS, et al. Hepatology. 2009;50: Weinbaum CM, et al. MMWR Recomm Rep. 2008:57 (RR-8): Weinbaum CM, et al. Hepatology. 2009:49(suppl 5):S35-S EASL. J Hepatol. 2009;50:

28 What Does ASCO Say? Evidence is insufficient to determine the net benefits and harms of routine screening for chronic HBV infection... Physicians may consider screening... groups at heightened risk for chronic HBV infection or if highly immunosuppressive therapy is planned... antiviral therapy before and throughout the course of chemotherapy may be considered... Artz AS, et al. J Clin Oncol. 2010;28:

29 Incremental Cost for Screen All vs Screen None Cost-effectiveness of HBV Screening Before R-CHOP for Lymphoma 50 Threshold (0.2%) United States (0.42%) Australia (1.1%) Canada (1.26%) Screen = HBsAg Population HBsAg Prevalence (%) -50 Strategy Cost, $ 1-Yr Survival, % Screen all 31, Screen high risk 31, Screen none 31, Screen all dominates other strategies less costly, more effective Zurawska U, et al Sep 10;30(26):

30 Screening Cost Effectiveness non-haem Solid Tumors Adjuvant = chemo for early breast cancer Palliative = chemo for non small cell lung cancer * Threshold of $50,000 AUD per LY saved Screen = HBsAg + antihbc Day. J Clin Oncol. 2011; 29 (24):

31 Screening Cost Effectiveness non-haem Solid Tumors Day. J Clin Oncol. 2011; 29 (24):

32 What Is Currently Being Done? National survey of Medical Oncology Group of Australia 188 responses (63%) 53% ever screen Only 19% screen all patients 65% of those who screen do so only in subgroups, especially due to ethnicity (82%) Day. J Oncol Pract. 2011; 7 (3) : 141-7

33 Significance of Lone Anti-HBc Positive Marker Indicates exposure to HBV Usually persists lifelong but may lose after yrs May be false positive if truly no HBV risk factors Risk for reactivation Low risk for most standard solid tumor regimens Consider preemptive HBV therapy if cirrhosis Consider preemptive HBV therapy highly immunosuppressive treatment strategies are used Rituximab Bone marrow/stem cell transplantation Manzano-Alonso ML, et al. World J Gastroenterol. 2011;17:

34 Rituximab: A Particular Problem Monoclonal antibody against CD20 (B-cell marker) Reduces B-cell numbers and antibody levels Used as part of CHOP-R for B cell malignancies Increasing use in non malignant conditions Increased risk of HBV reactivation, including HBsAgnegative patients Yeo W, et al. Hepatology. 2006;43: Papamichalis P, et al. Clin Res Hepatol Gastroenterol. 2012;36:84-93.

35 Proportion of Anti-HBc Positive, HBsAg-Negative Patients (%) HBV Reactivation With Rituximab in HBsAg-Negative Individuals Patients with diffuse large B-cell lymphoma HBsAg-negative, anti-hbc positive individuals treated with CHOP or CHOP-R Yeo W, et al. J Clin Oncol. 2009;27: HBV Reverse Seroconversion CHOP (n = 25) CHOP-R (n = 21) Risk Factors for reactivation 1. Men >> women (almost all cases) 2. Anti-HBs negative (or low titer) 3.? increased age (> 50 yrs) HBV-Related Death Risk of reactivation with rituximab significant in anti-hbc positive 5

36 Rituximab in HBsAg neg/anti-hbc pos 63 patients monitored prospectively q 4w for 2years Cumulative reactivation rate at 2 y = 41.5% Median 23 weeks post Rx (range 4-100) Median HBV VL 43 IU/ml (14-920) All normal ALT at reactivation Controlled by ETV in all cases Significantly associated only with baseline antihbs < 10 IU/ml HR 3.51, 95 CI , p=0.009 Seto W, et al. J Clin Oncol. 2014; 32 (33): HBV VL < 10 IU/ml

37 Conclusions Reactivation in HBsAg+ patients receiving cytotoxic chemo is common It can have devastating consequences if missed Screening is recommended (some targeted while others universal) but is not done well Universal screening for HBsAg is cost effective, role of anti HBc less clear Antiviral prophylaxis is effective and should be routine

38 Conclusions There is currently insufficient evidence to support routine prophylaxis of HBsAg -/anti HBc+ patients There may be a higher rate of reactivation in HBsAg neg/antihbc+ patients receiving rituximab and allogeneic HSCT recipients and prophylaxis may be warranted in these patients, particularly if anti-hbs neg

39 Thank You!