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Hepatitis B infection: An Under- Recognized Problem in Oncology Atif Zaman MD MPH Professor of Medicine Division of Gastroenterology and Hepatology. Case Presentation. 66 year old male who presented for evaluation of severe shoulder and chest pain.

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Case Presentation

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  1. Hepatitis B infection: An Under- Recognized Problem in OncologyAtif Zaman MD MPHProfessor of MedicineDivision of Gastroenterology and Hepatology

  2. Case Presentation • 66 year old male who presented for evaluation of severe shoulder and chest pain. • Medical history significant for amelanotic spindle cell melanoma (0.90mm, Clarks III-IV) on the left cheek, s/p excision in February 2007 • Presented to urgent care, CXR and subsequent chest CT abnormal: • CT chest: Numerous skeletal lesions (in bilateral ribs, vertebral bodies, and sternum) with the largest lytic mass involving the right 8th rib and posterior elements of T8 on the right with encroachment into the pleural space of the right lung and into the right paraspinous musculature. No pulmonary nodules. In accord with ORS.41675 related to QA, Teaching & Supervision of Medical Staff Physicians

  3. Case Presentation • PET scan revealed: Multifocal hypermetabolic activity throughout the axial and appendicular skeleton, with soft tissue masses at right T8 costovertebral junction (SUV 25) and costochondral junction of the right second rib. • CT-guided biopsy:Plasma cell neoplasm • Laboratory studies: SPEP: IgG kappa monoclonal protein detected; M-protein = 2.2 g/dL. B-2-M: 3.3, alb 3.9, Hb 14.4, Cr 0.99, Ca 9.7. • Bone marrow biopsy: 50-60% plasma cells • Karyotype and FISH: Karyotype normal, FISH 10% cells deletion 13. In accord with ORS.41675 related to QA, Teaching & Supervision of Medical Staff Physicians

  4. Case Presentation • Salmon-Durie Stage IIIA, ISS 1 • Chemotherapeutic regimens: • 6 cycles of DVD from 4/11 - 9/11 (modified due to Doxil shortage) • In 10/11 he received XRT 30Gy to R T8/rib lesion and R humerus • In 11/11 Restaging studies found PR, collected stem cells. Precollection standard studies found HepBcAB+, viral load undetectable • began maintenance VD q2 weeks + methylpred 20 q2day • BACBADAT (Bortezomib, Ascorbic acid, cytoxan, biaxin, acyclovir, dexamethasone, ASA, thalidomide) on 6th cycle WHEN… In accord with ORS.41675 related to QA, Teaching & Supervision of Medical Staff Physicians

  5. Case- continued • Early August : • Darkening of urine • Labs revealed acute hepatitis with marked elevation of transaminases, mildly elevated bilirubin. • Patient has been on Zetia and Crestor, concerned this is the main cause, but additional concerns include viral hepatitis reactivation vs. other medications vs. other viral causes. In accord with ORS.41675 related to QA, Teaching & Supervision of Medical Staff Physicians

  6. Laboratory Testing In accord with ORS.41675 related to QA, Teaching & Supervision of Medical Staff Physicians

  7. Case-continued • With HBsAg now positive HBV oral agent was started ASAP (HBV DNA level was still pending) • By two weeks… In accord with ORS.41675 related to QA, Teaching & Supervision of Medical Staff Physicians

  8. Laboratory Testing In accord with ORS.41675 related to QA, Teaching & Supervision of Medical Staff Physicians

  9. What is Going on Here?! • Did somebody drop the ball? • Did this patient actually have chronic HBV infection prior to therapy and was it missed? • Should this patient have been preemptively started on HBV meds, nucleoside analogues (NAs)? • How closely should this patient be monitored during chemotherapy? • This patient did well, but what if he went into liver failure?

  10. Hepatitis B: Some Sobering Facts • 350 million people chronically infected • 2 billion with evidence of past or present infection • Country of origin is THE major risk factor Prevalence of HBsAg High ≥ 8% Intermediate 2% to 7% Low < 2% World Health Organization. Hepatitis B Fact Sheet. Centers for Disease Control and Prevention. CDC Health Information for International Travel 2012. New York: Oxford University Press; 2012.

  11. Typical Interpretation ofSerologic Test Results for HBV Infection Modified from Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

  12. Natural History of Chronic HBV Infection Immune Control (Nonreplicative) Immunotolerance Immune Clearance HBV DNA HBeAg+ HBeAg- HBeAb+ HBsAg+ HBsAg- HBsAb+ ALT 5-30 Yrs Mos-Yrs Mos-Yrs Infection Yim HJ, et al. Hepatology. 2006;43:S173-S181.

  13. HBeAg+ HBeAg- HBeAb+ Natural History of Chronic HBV Infection Immune Control (Nonreplicative) Immunotolerance Immune Clearance HBV DNA • Most Oncology Patients • Normal ALT • Low/undetectable HBV DNA • HBsAg+ and HBeAg- • or HBsAg-, anti-HBc+ HBsAg+ HBsAg- HBsAb+ ALT 5-30 Yrs Mos-Yrs Mos-Yrs Infection Yim HJ, et al. Hepatology. 2006;43:S173-S181.

  14. Do You Ever Really Get Rid of HBV? • Immune control—not clearance • “Resolved HBV” a misnomer—still HBV DNA in liver • ccDNA—episomal replicative intermediate responsible for persistent infection of hepatocytes cccDNA Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.

  15. T cell T cell T cell Do You Ever Really Get Rid of HBV? • Immune control—not clearance • “Resolved HBV” a misnomer—still HBV DNA in liver cccDNA Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.

  16. T cell T cell T cell Along Comes Immune Suppression • Immune control can be lost • Immune-mediated liver damage with immune reconstitution HIV Steroids Chemotx cccDNA Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.

  17. T cell T cell T cell Along Comes Immune Suppression • Immune control can be lost • Immune-mediated liver damage with immune reconstitution HIV Steroids Chemotx cccDNA Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.

  18. HBV Reactivation HBeAg+ HBeAg- HBeAb+ HBeAg+ Immunotolerance Immune Clearance HBV DNA ALT 5-30 Yrs Mos-Yrs Mos-Yrs Infection Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.

  19. HBV Reactivation HBeAg+ HBeAg- HBeAb+ HBeAg+ Immunotolerance Immune Suppression Immune Clearance HBV DNA ALT 5-30 Yrs Mos-Yrs Mos-Yrs Infection Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.

  20. HBV Reactivation HBeAg+ HBeAg- HBeAb+ HBeAg+ Immunotolerance Immune Suppression Immune Reconstitution Immune Clearance HBV DNA ALT 5-30 Yrs Mos-Yrs Mos-Yrs Infection Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.

  21. 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 • Range from subclinical to severe/fatal hepatitis • Rise in HBV DNA ± return of HBeAg • ALT increase (may be mild or very dramatic) • May progress to liver failure/death despite antiviral therapy Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.

  22. Subset of Agents Reported to Cause HBV Reactivation Yeo W, et al. Hepatology. 2006;43:209-220.

  23. Consequences of Delayed Recognition of HBV Reactivation Hepatitis • May be severe or even fulminant • Occasionally may miss HBV DNA spike because HBV DNA may fall when ALT rises • This may lead to misdiagnosis and, ultimately, may result in subsequent flares of HBV • By the time ALT rises . . . may be too late to bring under control Interruption of chemotherapy • Potential for poorer cancer-related outcome Yeo W, et al. Hepatology. 2006;43:209-220.

  24. 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;22:237-243.2. Yeo W, et al. J Med Virol. 2003;70:553-561.

  25. Hematologic Malignancy: The Bigger Risk 100 patients with NHL undergoing CHOP; 27 HBsAg positive 100 80 60 48 HBsAg Patients (%) 40 22 20 4 4 0 HBV Reactivation Jaundice Nonfatal Liver Failure Death Lok AS, et al. Gastroenterology. 1991;100:182-188.

  26. Risk Factors for HBV Reactivation • Malignancy • NHL: 40% to 58% of HBsAg positive • Breast cancer: up to 41% of HBsAg positive • Chemotherapy • Prednisone, anthracyclines, rituximab increased risk • “Potency of immunosuppression” • HBV DNA • HBV DNA > 3 × 105 copies/mL • Elevated if HBeAg positive • Demographics • Men > women Yeo W, et al. Hepatology. 2006;43:209-220.

  27. Steroids Increase Risk of HBV Reactivation • 50 patients with NHL who were HBsAg positive randomized to epirubicin, cyclophosphamide and etoposide (ACE) ± prednisolone (P) ACE 100 PACE 73* 80 68 *P < .05 60 46 44* HBsAg Patients (%) 38 36 35 40 * 28* 13 20 4 0 HBV Reactivation ALT > 10 x ULN Jaundice Complete Remission Survival at 4 Yrs Prednisolone increased risk and severity of HBV reactivation but trend toward improved NHL outcome Cheng AL, et al. Hepatology. 2003;37:1320-1328.

  28. BOISE TO PORTLAND….STRAIGHT

  29. WHAT DO THE VARIOUS GUIDELINES SAY?

  30. What Does American Society of Clinical Oncology (ASCO) Say about HBV Screening Prior to Chemotherapy? • “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;28:3199-3202.

  31. Evaluating ASCO’s Position • Evidence for antiviral therapy weak: small studies, questionable effect on mortality • Small studies but very strong effect and assessed TIMING, not value of therapy • RCTs of screening vs no screening very uncommon • Cost of screening and delay in starting chemotherapy • HBsAg costs $13 • No need to delay chemotherapy for results of HBV testing • Antiviral therapy: safety and drug interactions • Very safe • No effect on chemotherapy pharmacokinetics Artz AS, et al. J Clin Oncol. 2010;28:3199-3202.

  32. 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;50:661-662.

  33. 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 CDC[2,3] & EASL[4] recommend screening ALL patients prior to starting chemotherapy 1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. Weinbaum CM, et al. MMWR Recomm Rep. 2008:57(RR-8):1-20. 3. Weinbaum CM, et al. Hepatology. 2009:49(suppl 5):S35-S44. 4. EASL. J Hepatol. 2012;57:167-185.

  34. What Is Currently Being Done? Chart Review of Actual Screening (208 Pts at Single Institution)[2] Self-Reported HBV Screening Practices of 131 US Oncologists[1] 100 80 62 60 HBV Screening (%) 40 24 14 14 20 0 None High Risk All ActualScreening Rate Few oncologists routinely screen all patients initiating chemotherapy for HBV 1. Khokhar OS, et al. Chemotherapy. 2009;55:69-75. 2. Lee R, et al. Curr Oncol. 2010;17:32-38.

  35. Is Screening Only of High-Risk Populations Effective? Knowledge About HBV ScreeningAmong Oncologists 100 80 60 Proportion of Oncologists (%) 40 20 0 Recognize Country of Origin as No. 1 Risk Factor Aware of HBVGuidelines High-risk screening requires recognition of high-risk population Lee R, et al. ASCO 2010. Abstract 6147.

  36. What Is the Optimal Screening Strategy? • Screening all patients is most cost-effective and easiest to implement • HBsAg should be tested in all individuals, with follow-up HBV DNA in HBsAg-positive 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. 2012;57:167-185. 2. Lok AS, et al. Hepatology. 2009;50:661-662. 3. Weinbaum CM, et al. Hepatology. 2009:49(suppl 5):S35-S44. 4. Artz AS, et al. J Clin Oncol. 2010;28:3199-3202.

  37. Treatment and Prevention of HBV Reactivation

  38. Use of Preemptive Lamivudine Reduces Risk of HBV-Related Hepatitis • HBsAg-positive patients with lymphoma treated with high-dose chemotherapy randomized to “preemptive” vs “on-demand” lamivudine 100 Preemptive LAM 75 Survival Free From Hepatitis Due to HBV Reactivation 50 P = .002 by log-rank test On-demand LAM (if HBV DNA increased) 25 0 0 10 20 30 40 Wk Pts at Risk, nPreemptive LAM On-demand LAM 1515 1213 1010 94 62 Lau GK, et al. Gastroenterology. 2003;125:1742-1749.

  39. Value of Preemptive Antivirals • HBsAg-positive patients with NHL treated with CHOP randomized to “preemptive” vs “on-demand” lamivudine 100 On-demand group: start LAM if ALT > 1.5 x ULN Preemptive group: start LAM on Day 1 of CHOP 80 60 48 HBsAg Patients (%) 36 40 20 20 8 8 0 0 0 0 HBV Reactivation and Hepatitis Flare HBV Reactivation and ALT >10 x ULN HBV Reactivationand Jaundice Death (After ChemoTx) Preemptive antivirals decrease HBV reactivation Hsu C, et al. Hepatology. 2008;47:844-853.

  40. 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. 2012;57:167-185. Lok AS, et al. Hepatology. 2009;50:661-662.

  41. 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. 2012;57:167-185. Lok AS, et al. Hepatology. 2009;50:661-662.

  42. BAMBI AND THE WOLF

  43. What About Our Case of Isolated HBcAb-positivity?

  44. Significance of Isolated 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 • No guidelines for management • Risk for reactivation • Low risk for most standard solid tumor regimens • Consider preemptive HBV therapy if cirrhosis is present • Consider preemptive HBV therapy if the following treatment strategies are used • Rituximab • Bone marrow/stem cell transplantation Manzano-Alonso ML, et al. World J Gastroenterol. 2011;17:1531-1537.

  45. Rituximab: A Particular Problem • Monoclonal antibody against CD20 (B-cell marker) • Reduces B-cell numbers and antibody levels • Increasingly used as part of CHOP-R, EPOCH-R • Increased risk of HBV reactivation, including HBsAg-negative patients • Reverse seroconversion: reappearance of HBsAg in previously HBsAg-negative patient due to loss of immune control Yeo W, et al. Hepatology. 2006;43:209-220. Papamichalis P, et al. Clin Res Hepatol Gastroenterol. 2012;36:84-93.

  46. 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 40 CHOP (n = 25) CHOP-R (n = 21) 30 24 Proportion of Anti-HBc Positive, HBsAg-Negative Patients (%) 20 10 5 0 0 0 HBV-Related Death HBV Reverse Seroconversion Risk of reactivation with rituximab significant in anti-HBc positive Yeo W, et al. J Clin Oncol. 2009;27:605-611.

  47. HBV Reactivation Associated With Rituximab: Typically Late and Severe • Reverse HBV seroconversion[1] • Among 5 patients who reactivated, 1 during fifth cycle of chemotherapy; 3 median of 98 days AFTER last rituximab cycle; can occur early as well • Median peak ALT: 809 U/L (362-3499) • Median peak bilirubin: 65 µmol/L (19-249) • Additional cases reported in literature • Including instances of liver failure and liver-related deaths • Risk Factors for reactivation • Men >> women (almost all cases) • Anti-HBs negative (or low titer) • ? increased age (> 50 yrs) Yeo W, et al. J Clin Oncol. 2009;27:605-611.

  48. Bone Marrow Transplantation: Increased Risk of Reactivation • Markedly high rate of reactivation (HBsAg positive) • Up to 54%[1]→ need preemptive antiviral therapy! • Long-term complications: cirrhosis in 10%[2] • Reverse seroconversion common if anti-HBc positive[3] • Up to 50% become HBsAg positive → use preemptive antivirals • May occur very late • HBV status of donor important[1,4] • If natural immunity (anti-HBs, anti-HBc): may clear HBsAg • If vaccinated (anti-HBs): possibly some protection 1. Lau GK, et al. Bone Marrow Transplant. 1997;19:795-799. 2. Hui CK, et al. Blood. 2005;106:464-469.3. Onozawa M, et al. Transplantation. 2005;79:616-619. 4. Lau GK, et al. J Infect Dis. 1998;178:1585-1591.

  49. CANADA DOWN THE DRAIN

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