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.

 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 Physician s

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 Physician s

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 6 th cycle WHEN… In accord with ORS.41675 related to QA, Teaching & Supervision of Medical Staff Physician s

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 Physician s

Laboratory Testing

ALT AST Total Bilirubin Albumin INR HBsAg HBsAb HBcAb HBV DNA

Pre Chemotherapy

20 32 1.2

3.5

1.03

negative negative positive undetectable

During Chemo Therapy (7/20/12)

77

At the time of Acute Hepatitis 8/2012)

2506 1473 2.2

3.4

1.14

positive negative positive 360 IU/mL In accord with ORS.41675 related to QA, Teaching & Supervision of Medical Staff Physician s

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 Physician s

Laboratory Testing

ALT AST Total Bilirubin Albumin INR HBsAg HBsAb HBcAb HBV DNA

During Chemo Therapy (7/20/12)

77

At the time of Acute Hepatitis 8/2012)

2506 1473 2.2

3.4

1.14

positive negative positive 360 IU/mL

On HBV oral med (9/2012)

28 26 1.1

3.4

1.06

undetectable In accord with ORS.41675 related to QA, Teaching & Supervision of Medical Staff Physician s

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?

Hepatitis B: Some Sobering Facts Prevalence of HBsAg

High ≥ 8% Intermediate 2% to 7% Low < 2%    350 million people chronically infected 2 billion with evidence of past or present infection Country of origin is THE major risk factor 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.

Typical Interpretation of Serologic Test Results for HBV Infection HBs Ag Serologic Marker Results Total Anti-HBc IgM Anti-HBc Anti HBs Interpretation Never infected and no evidence of immunization Acute infection + + + + + + + + + Chronic infection Exposure, false positive or chronic infection Exposure and clearance of HBV infection Immune (immunization)

Modified from Weinbaum CM, et al. MMWR Recomm Rep.

2008;57(RR-8):1-20.

Natural History of Chronic HBV Infection Immunotolerance HBV DNA Immune Clearance Immune Control (Nonreplicative)

HBeAg+ HBsAg+

ALT 5-30 Yrs Mos-Yrs Infection

Yim HJ, et al. Hepatology. 2006;43:S173-S181.

HBeAg HBeAb+ HBsAg- HBsAb +

Mos-Yrs

Natural History of Chronic HBV Infection Immunotolerance HBV DNA Immune Clearance

HBeAg+ HBsAg+

ALT Immune Control (Nonreplicative) Most Oncology Patients

 Normal ALT  Low/undetectable HBV DNA   HBsAg+ and HBeAg or HBsAg-, anti-HBc+ HBeAg HBeAb+ HBsAg- HBsAb +

5-30 Yrs Mos-Yrs Infection

Yim HJ, et al. Hepatology. 2006;43:S173-S181.

Mos-Yrs

Do You Ever Really Get Rid of HBV?

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

Do You Ever Really Get Rid of HBV?

T cell cccDNA T cell  Immune control —not clearance  “Resolved HBV” a misnomer—still HBV DNA in liver Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.

T cell

Along Comes Immune Suppression

T cell cccDNA T cell T cell  Immune control can be lost  Immune-mediated liver damage with immune reconstitution Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.

HIV Steroids Chemotx

Along Comes Immune Suppression

T cell cccDNA T cell T cell  Immune control can be lost  Immune-mediated liver damage with immune reconstitution Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.

HIV Steroids Chemotx

HBV Reactivation HBeAg+

Immunotolerance Immune Clearance

HBeAg HBV DNA HBeAb+ HBeAg+ ALT 5-30 Yrs Mos-Yrs Infection

Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.

Mos-Yrs

HBV Reactivation HBeAg+

Immunotolerance Immune Clearance

HBeAg HBeAb+ Immune Suppression HBV DNA HBeAg+ ALT 5-30 Yrs Mos-Yrs Infection

Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.

Mos-Yrs

HBV Reactivation HBeAg+

Immunotolerance Immune Clearance

HBeAg HBeAb+ Immune Suppression HBV DNA HBeAg+ Immune Reconstitution ALT 5-30 Yrs Mos-Yrs Infection

Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.

Mos-Yrs

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.

Subset of Agents Reported to Cause HBV Reactivation Class

Corticosteroids Antitumor antibiotics Plant alkaloids Alkylating agents Antimetabolites Monoclonal antibodies Others

Agents

Dexamethasone, methylprednisolone, prednisolone Actinomycin D, bleomycin, daunorubicin, doxorubicin, epirubicin, mitomycin-C Vinblastine, vincristine Carboplatin, chlorambucil, cisplatin, cyclophosphamide, ifosfamide Azauridine, cytarabine, fluouracil, gemcitabine, mercaptopurine, methotrexate, thioguanine Alemtuzumab, rituximab Colaspase, docetaxel, etoposide, fludarabine, folinic acid, interferon, procarbazine Yeo W, et al. Hepatology. 2006;43:209-220.

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.

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.

Hematologic Malignancy: The Bigger Risk

100 patients with NHL undergoing CHOP; 27 HBsAg positive 100 80 60

48

40

22

20

4

0

HBV Reactivation Jaundice Nonfatal Liver Failure

Lok AS, et al. Gastroenterology. 1991;100:182-188.

4 Death

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 ” Yeo W, et al. Hepatology. 2006;43:209-220.

 HBV DNA – HBV DNA > 3 × 10 5 copies/mL – Elevated if HBeAg positive  Demographics – Men > women



Steroids Increase Risk of HBV Reactivation

50 patients with NHL who were HBsAg positive randomized to epirubicin, cyclophosphamide and etoposide (ACE) ± prednisolone (P) 100 ACE PACE 80

73* 68

60 *

P

< .05

40

38 44* 28*

*

35 46 36

20

13 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.

BOISE TO PORTLAND….STRAIGHT

WHAT DO THE VARIOUS GUIDELINES SAY?

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.

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.

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.

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;50:661-662. 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.

What Is Currently Being Done?

100

Self-Reported HBV Screening Practices of 131 US Oncologists [1] Chart Review of Actual Screening (208 Pts at Single Institution) [2]

80

62

60 40 20

24 14 14

0

None High Risk All Actual Screening 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.

Is Screening Only of High-Risk Populations Effective?

Knowledge About HBV Screening Among Oncologists

100 80 60 40 20 0

Recognize Country of Origin as No. 1 Risk Factor Aware of HBV Guidelines High-risk screening requires recognition of high-risk population

Lee R, et al. ASCO 2010. Abstract 6147.

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.

Treatment and Prevention of HBV Reactivation



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 50 25

P

= .002 by log-rank test

On-demand LAM (if HBV DNA increased)

0 0 10

Pts at Risk, n

Preemptive LAM On-demand LAM 15 15 12 13 Lau GK, et al. Gastroenterology. 2003;125:1742-1749.

20

Wk

10 10 30 9 4 40 6 2

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

40

36 20

20

8

0

HBV Reactivation and Hepatitis Flare 0 0 HBV Reactivation and ALT >10 x ULN HBV Reactivation and Jaundice 8 0 Death (After ChemoTx) Preemptive antivirals decrease HBV reactivation

Hsu C, et al. Hepatology. 2008;47:844-853.



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.

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.

BAMBI AND THE WOLF

What About Our Case of Isolated HBcAb-positivity?

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.

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.



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 30 CHOP (n = 25) CHOP-R (n = 21)

24

20 10

5 0 0

0

HBV Reverse Seroconversion HBV-Related Death Risk of reactivation with rituximab significant in anti-HBc positive

Yeo W, et al. J Clin Oncol. 2009;27:605-611.



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)

Risk Factors for reactivation

1. Men >> women (almost all cases) 2. Anti-HBs negative (or low titer) 3. ? increased age (> 50 yrs) Additional cases reported in literature – Including instances of liver failure and liver-related deaths Yeo W, et al. J Clin Oncol. 2009;27:605-611.



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.

CANADA DOWN THE DRAIN

WHAT DO THE VARIOUS GUIDELINES SAY?

What Does ASCO 2010 Say About Isolated HBcAb Positivity?

No comment



What Does AASLD 2009 Say About Isolated HBcAb Positivity?

“While HBV reactivation can occur in persons who are HBsAg negative but … with isolated anti-HBc, this is infrequent, and there is not enough information to recommend routine prophylaxis for these individuals”



What Does EASL 2012 Say About Isolated HBcAb Positivity?

Should be tested for HBV DNA – Patients with detectable serum HBV DNA should be treated similarly to HBsAg positive patients – Patients with undetectable serum HBV DNA undetectable serum HBV DNA who receive chemotherapy and/or immunosuppression should be followed carefully by means of ALT and HBV DNA testing q1-3 months and treated with NA therapy upon confirmation of HBV reactivation before ALT elevation – HOWEVER… some experts recommend preemptive NA therapy in all who receive rituximab and/or combined regimens for hematological malignancies, bone marrow and stem cell transplants

So Who Dropped the Ball in Our Case?

  No one in particular BUT the guidelines are outdated (esp the oncology guidelines) and non-committal in regards to isolated HBcAb  March 2013 there will be a combined AASLD/NIH sponsored conference on this topic  Until then…

Recommendations

 Preemptive therapy requires preemptive screening , which is highly cost-effective  Screening recommended by CDC, EASL, AASLD, and IOM – Patients to receive S tandard chemotherapy – Screen HBsAg ( ± anti-HBc) – Patients to receive C omplex chemotherapy (eg, rituximab/ BMT) – Screen HBsAg, anti-HBc, anti-HBs

Summary: Screening Tests and Results Test

HBsAg Anti-HBs alone Anti-HBc anti-HBs ±

Significance

HBV infection Immunity to HBV Exposure to HBV

Action

Prophylaxis indicated None  **low risk for standard chemotherapy, monitor  If rituximab and/or combined regimens for hematological malignancies or BMT or cirrhotic, prophylaxis indicated HBV DNA  Undetectable  < 2000 IU/mL  ≥ 2000 IU/mL Very low HBV DNA Low HBV DNA High HBV DNA Lamivudine adequate Lamivudine adequate Tenofovir or Entecavir **If observation is chosen, monitor liver tests, HBsAg and HBV DNA q1-3 months