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

Hepatitis B infection: An Under- Recognized Problem in Oncology

Atif Zaman MD MPHProfessor 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 Physicians

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.


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…


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.


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


Case-continued

With HBsAg now positive HBV oral agent was started ASAP (HBV DNA level was still pending)

By two weeks…


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


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

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.

Prevalence of HBsAg

High ≥ 8%Intermediate 2% to 7%Low < 2%

Typical Interpretation ofSerologic Test Results for HBV Infection

Serologic Marker Results

HBsAg

TotalAnti-HBc

IgMAnti-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

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

HBeAg+ HBeAg- HBeAb+

Immune ClearanceImmunotolerance

ALT

HBV DNA

Mos-Yrs

Immune Control(Nonreplicative)

HBsAg+ HBsAg- HBsAb+

Infection

Mos-Yrs5-30 Yrs

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

Immune ClearanceImmunotolerance

ALT

HBV DNA

Mos-Yrs

HBsAg+ HBsAg- HBsAb+

Infection

Mos-Yrs5-30 Yrs

Natural History of Chronic HBV Infection

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

Immune Control(Nonreplicative)

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.

Do You Ever Really Get Rid of HBV?

Immune control—not clearance

“Resolved HBV” a misnomer—still HBV DNA in liver

T cell

T cell

T cell

cccDNA


Along Comes Immune Suppression

Immune control can be lost

Immune-mediated liver damage with immune reconstitution

HIVSteroidsChemotxT cell

T cell

T cell

cccDNA


Along Comes Immune Suppression

Immune control can be lost

Immune-mediated liver damage with immune reconstitution

HIVSteroidsChemotxT cell

T cell

T cell

cccDNA


HBV Reactivation

5-30 Yrs Mos-YrsInfection

ImmunotoleranceImmune Clearance


Mos-Yrs

ALT

HBV DNA

HBeAg+

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

HBV Reactivation

5-30 Yrs Mos-YrsInfection



Mos-Yrs

ALT

HBV DNA

HBeAg+

Immune Suppression


HBV Reactivation

Infection



ALT

HBV DNA

HBeAg+

Immune Suppression Immune Reconstitution


5-30 Yrs Mos-Yrs 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


Subset of Agents Reported to Cause HBV Reactivation

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

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

Consequences of Delayed Recognition of HBV ReactivationHepatitis

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


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

HBV Reactivation

Jaundice NonfatalLiver Failure

Death

100 patients with NHL undergoing CHOP; 27 HBsAg positive

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

HB

sAg

Pat

ien

ts (

%)

100

80

60

40

20

0

48

22

4 4

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


Steroids Increase Risk of HBV Reactivation 50 patients with NHL who were HBsAg positive randomized to epirubicin,

cyclophosphamide and etoposide (ACE) ± prednisolone (P)

Cheng AL, et al. Hepatology. 2003;37:1320-1328.

HBV Reactivation

Jaundice Survivalat 4 Yrs

ALT> 10 x ULN

CompleteRemission

*

*P < .05

Prednisolone increased risk and severity of HBV reactivationbut trend toward improved NHL outcome

HB

sAg

Pat

ien

ts (

%)

100

80

60

40

20

0

38

73*

13

44*

4

28*35

4636

68

ACEPACE

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?

Lok AS, et al. Hepatology. 2009;50:661-662.

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

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.

What Is Currently Being Done?

1. Khokhar OS, et al. Chemotherapy. 2009;55:69-75. 2. Lee R, et al. Curr Oncol. 2010;17:32-38.

Self-Reported HBV Screening Practices of 131 US Oncologists[1]

Chart Review of Actual Screening (208 Pts at Single

Institution)[2]

Few oncologists routinely screen all patients initiating chemotherapy for HBV

HB

V S

cree

nin

g (

%)

60

40

20

0None High Risk All Actual

Screening Rate

62

2414 14

80

100

Is Screening Only of High-Risk Populations Effective?

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

High-risk screening requires recognition of high-risk population

Pro

po

rtio

n o

f O

nco

log

ists

(%

)

60

40

20

0Recognize Country of Origin as No. 1

Risk Factor

Aware of HBVGuidelines

80

100

Knowledge About HBV ScreeningAmong Oncologists

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

On-demand LAM(if HBV DNA increased)

Su

rviv

al F

ree

Fro

m H

epat

itis

D

ue

to H

BV

Rea

ctiv

atio

n

Lau GK, et al. Gastroenterology. 2003;125:1742-1749.

Preemptive LAM100

75

50

25

00 10 20 30 40

Wk

P = .002 by log-rank test

Pts at Risk, nPreemptive LAMOn-demand LAM

1515

1213

1010

94

62

Value of Preemptive Antivirals

HBsAg-positive patients with NHL treated with CHOP randomized to “preemptive” vs “on-demand” lamivudine

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

On-demand group: start LAM if ALT > 1.5 x ULN Preemptive group: start LAM on Day 1 of CHOP

Preemptive antivirals decrease HBV reactivation

HBV Reactivation and Hepatitis Flare

HBV Reactivationand Jaundice

HBV Reactivation and ALT >10 x ULN

Death(After ChemoTx)

100

80

60

40

20

0

HB

sAg

Pa

tie

nts

(%

)

48

8

36

0

20

0 08

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 transplantationManzano-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

HBV ReverseSeroconversion

HBV-RelatedDeath

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

Risk of reactivation with rituximab significant in anti-HBc positive

40

30

20

10

0

24

0 05P

rop

ort

ion

of

An

ti-H

Bc

Po

siti

ve,

HB

sAg

-Neg

ativ

e P

atie

nts

(%

)

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

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

Risk Factors for reactivation1.Men >> women (almost all cases)2.Anti-HBs negative (or low titer)3.? increased age (> 50 yrs)

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 protection1. 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?

No comment

What Does ASCO 2010 Say About Isolated HBcAb Positivity?

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 Standard chemotherapy

– Screen HBsAg (± anti-HBc)

– Patients to receive Complex chemotherapy (eg, rituximab/ BMT)

– Screen HBsAg, anti-HBc, anti-HBs

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 DNAUndetectable< 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

Documents

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