Hepatitis B infection: An Under- Recognized Problem in Oncology Atif Zaman MD MPH Professor of Medicine Division of Gastroenterology and Hepatology

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 biopsyPlasma 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
Pre-Chemotherapy During Chemo-Therapy (7/20/12) At the time of Acute Hepatitis 8/2012)
ALT 20 77 2506
AST 32 1473
Total Bilirubin 1.2 2.2
Albumin 3.5 3.4
INR 1.03 1.14
HBsAg negative positive
HBsAb negative negative
HBcAb positive positive
HBV DNA undetectable 360 IU/mL
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
During Chemo-Therapy (7/20/12) At the time of Acute Hepatitis 8/2012) On HBV oral med (9/2012)
ALT 77 2506 28
AST 1473 26
Total Bilirubin 2.2 1.1
Albumin 3.4 3.4
INR 1.14 1.06
HBsAg positive
HBsAb negative
HBcAb positive
HBV DNA 360 IU/mL undetectable
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?

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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

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.
12
Typical Interpretation ofSerologic Test Results
for HBV Infection
Serologic Marker Results Serologic Marker Results Serologic Marker Results Serologic Marker Results
HBsAg 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. 200857(RR-8)1-20.
13
Natural History of Chronic HBV Infection
Immune Control (Nonreplicative)
Immune Clearance
Immunotolerance
HBV DNA
HBeAg HBeAg- HBeAb
HBsAg HBsAg- HBsAb
ALT
Mos-Yrs
Mos-Yrs
5-30 Yrs
Infection
Yim HJ, et al. Hepatology. 200643S173-S181.
14
Natural History of Chronic HBV Infection
Immune Control (Nonreplicative)
Immune Clearance
Immunotolerance
HBV DNA

• Most Oncology Patients
• Normal ALT
• Low/undetectable HBV DNA
• HBsAg and HBeAg-
• or HBsAg-, anti-HBc

HBsAg HBsAg- HBsAb
ALT
Mos-Yrs
Mos-Yrs
5-30 Yrs
Infection
Yim HJ, et al. Hepatology. 200643S173-S181.
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Do You Ever Really Get Rid of HBV?
cccDNA

• Immune controlnot clearance
• Resolved HBV a misnomerstill HBV DNA in liver
• ccDNAepisomal replicative intermediate
  responsible for persistent infection of
  hepatocytes

Werle-Lapostolle B, et al. Gastroenterology.
20041261750-1758.
16
Do You Ever Really Get Rid of HBV?
cccDNA

• Immune controlnot clearance
• Resolved HBV a misnomerstill HBV DNA in liver

Werle-Lapostolle B, et al. Gastroenterology.
20041261750-1758.
17
Along Comes Immune Suppression
HIV Steroids Chemotx
cccDNA

• Immune control can be lost
• Immune-mediated liver damage with immune
  reconstitution

Werle-Lapostolle B, et al. Gastroenterology.
20041261750-1758.
18
Along Comes Immune Suppression
HIV Steroids Chemotx
cccDNA

• Immune control can be lost
• Immune-mediated liver damage with immune
  reconstitution

Werle-Lapostolle B, et al. Gastroenterology.
20041261750-1758.
19
HBV Reactivation
HBeAg HBeAg- HBeAb
HBeAg
Immunotolerance
Immune Clearance
HBV DNA
ALT
5-30 Yrs
Mos-Yrs
Mos-Yrs
Infection
Hoofnagle JH. Hepatology. 200949(5
suppl)S156-S165.
20
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. 200949(5
suppl)S156-S165.
21
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. 200949(5
suppl)S156-S165.
22
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. 200949(5
suppl)S156-S165.
23
Subset of Agents Reported to Cause HBV
Reactivation
Class Agents
Corticosteroids Dexamethasone, methylprednisolone, prednisolone
Antitumor antibiotics Actinomycin D, bleomycin, daunorubicin, doxorubicin, epirubicin, mitomycin-C
Plant alkaloids Vinblastine, vincristine
Alkylating agents Carboplatin, chlorambucil, cisplatin, cyclophosphamide, ifosfamide
Antimetabolites Azauridine, cytarabine, fluouracil, gemcitabine, mercaptopurine, methotrexate, thioguanine
Monoclonal antibodies Alemtuzumab, rituximab
Others Colaspase, docetaxel, etoposide, fludarabine, folinic acid, interferon, procarbazine
Yeo W, et al. Hepatology. 200643209-220.
24
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. 200643209-220.
25
Rate of HBV Reactivation Solid Tumors

• HBsAg-positive breast cancer patients receiving
  chemotherapy
• Rate of HBV-associated acute hepatitis 211
• With careful HBV DNA monitoring, up to 41 with
  HBV reactivation2
• HBV DNA may be undetectable by time of ALT peak
• Limited data on other solid tumors

Of those who flare2 35 chemotherapy
interruption 35 premature termination of
chemotherapy
1. Kim MK, et al. Korean J Intern Med.
200722237-243.2. Yeo W, et al. J Med Virol.
200370553-561.
26
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. 1991100182-188.
27
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 gt 3 105 copies/mL
• Elevated if HBeAg positive
• Demographics
• Men gt women

Yeo W, et al. Hepatology. 200643209-220.
28
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 lt .05
60
46
44
HBsAg Patients ()
38
36
35
40

28
13
20
4
0
HBV Reactivation
Jaundice
Survival at 4 Yrs
ALT gt 10 x ULN
Complete Remission
Prednisolone increased risk and severity of HBV
reactivation but trend toward improved NHL outcome
Cheng AL, et al. Hepatology. 2003371320-1328.
29
BOISE TO PORTLAND.STRAIGHT
30
WHAT DO THE VARIOUS GUIDELINES SAY?
31
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. 2010283199-3202.
32
Evaluating ASCOs 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. 2010283199-3202.
33
Who Should Be Screened?

• AASLD recommends screening high-risk
  individuals1
• 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. 200950661-662.
34
Who Should Be Screened?

• AASLD recommends screening high-risk
  individuals1
• 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

CDC2,3 EASL4 recommend screening ALL
patients prior to starting chemotherapy
1. Lok AS, et al. Hepatology. 200950661-662. 2.
Weinbaum CM, et al. MMWR Recomm Rep.
200857(RR-8)1-20. 3. Weinbaum CM, et al.
Hepatology. 200949(suppl 5)S35-S44. 4. EASL. J
Hepatol. 201257167-185.
35
What Is Currently Being Done?
Self-Reported HBV Screening Practices of 131 US
Oncologists1
Chart Review of Actual Screening (208 Pts at
Single Institution)2
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.
20095569-75. 2. Lee R, et al. Curr Oncol.
20101732-38.
36
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.
37
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-HBc1
• AASLD HBsAg and anti-HBc2
• CDC HBsAg and anti-HBc and anti-HBs3
• ASCO Consider HBsAg alone4

1. EASL. J Hepatol. 201257167-185. 2. Lok AS,
et al. Hepatology. 200950661-662. 3. Weinbaum
CM, et al. Hepatology. 200949(suppl 5)S35-S44.
4. Artz AS, et al. J Clin Oncol.
2010283199-3202.
38
Treatment and Prevention of HBV Reactivation
39
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.
20031251742-1749.
40
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 gt 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 Reactivationand Jaundice
HBV Reactivation and ALT gt10 x ULN
Death (After ChemoTx)
Preemptive antivirals decrease HBV reactivation
Hsu C, et al. Hepatology. 200847844-853.
41
Choice of Antiviral Therapy and Monitoring

• Choice of therapy affected by HBV DNA level
• HBV DNA lt 2000 IU/mL any therapy can be used
  (including lamivudine)
• HBV DNA gt 2000 IU/mL entecavir or tenofovir
• Choice of therapy affected by duration of therapy
• gt 12 mos entecavir or tenofovir
• HBV DNA and ALT should be monitored every 3 mos

EASL. J Hepatol. 201257167-185. Lok AS, et al.
Hepatology. 200950661-662.
42
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 gt 2000 IU/mL high risk of
  withdrawal flare
• Continue therapy as for chronic HBV infection
• If baseline HBV DNA lt 2000 IU/mL
• 6-12 mos after end of chemotherapy
• Monitor for withdrawal flares with monthly HBV
  DNA and ALT

EASL. J Hepatol. 201257167-185. Lok AS, et al.
Hepatology. 200950661-662.
43
BAMBI AND THE WOLF
44
What About Our Case of Isolated HBcAb-positivity?
45
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.
2011171531-1537.
46
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. 200643209-220.
Papamichalis P, et al. Clin Res Hepatol
Gastroenterol. 20123684-93.
47
HBV Reactivation With Rituximab in HBsAg-Negative
Individuals

• Patients with diffuse large B-cell lymphoma
• HBsAg-negative, anti-HBcpositive 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 Reverse Seroconversion
HBV-Related Death
Risk of reactivation with rituximab significant
in anti-HBc positive
Yeo W, et al. J Clin Oncol. 200927605-611.
48
HBV Reactivation Associated With Rituximab
Typically Late and Severe

• Reverse HBV seroconversion1
• 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 gtgt women (almost all cases)
• Anti-HBs negative (or low titer)
• ? increased age (gt 50 yrs)

Yeo W, et al. J Clin Oncol. 200927605-611.
49
Bone Marrow Transplantation Increased Risk of
Reactivation

• Markedly high rate of reactivation (HBsAg
  positive)
• Up to 541 ? need preemptive antiviral therapy!
• Long-term complications cirrhosis in 102
• Reverse seroconversion common if anti-HBc
  positive3
• Up to 50 become HBsAg positive ? use preemptive
  antivirals
• May occur very late
• HBV status of donor important1,4
• 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.
199719795-799. 2. Hui CK, et al. Blood.
2005106464-469. 3. Onozawa M, et al.
Transplantation. 200579616-619. 4. Lau GK, et
al. J Infect Dis. 19981781585-1591.
50
CANADA DOWN THE DRAIN
51
WHAT DO THE VARIOUS GUIDELINES SAY?
52
What Does ASCO 2010 Say About Isolated HBcAb
Positivity?

• No comment

53
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

54
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

55
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

56
Recommendations

• Preemptive therapy requires preemptive screening,
  which is highly cost-effective
• Screening recommended by CDC, EASL, AASLD, and
  IOM
• Patients to receive Standard chemotherapy
• Screen HBsAg ( anti-HBc)
• Patients to receive Complex chemotherapy (eg,
  rituximab/ BMT)
• Screen HBsAg, anti-HBc, anti-HBs

57
Summary Screening Tests and Results
Test Significance Action
HBsAg HBV infection Prophylaxis indicated
Anti-HBs alone Immunity to HBV None
Anti-HBc anti-HBs Exposure to HBV low risk for standard chemotherapy, monitor If rituximab and/or combined regimens for hematological malignancies or BMT or cirrhotic, prophylaxis indicated
HBV DNA Undetectable lt 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