Transcript Hepatitis B Reactivation: A Largely Preventable Problem

Hepatitis B infection: An UnderRecognized 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 6th 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
PreChemotherapy
During ChemoAt the time of
Therapy (7/20/12) Acute Hepatitis
8/2012)
ALT
20
77
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
2506
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
During
ChemoTherapy
(7/20/12)
At the time of
Acute Hepatitis
8/2012)
On HBV oral med
(9/2012)
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
ALT
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
Serologic Marker Results
HBs
Ag
Total
IgM
AntiAnti-HBc Anti-HBc HBs
Interpretation
-
-
-
-
Never infected and no evidence of
immunization
+
+
-
+
+
+
+
-
-
Acute infection
-
+
-
-
+
+
Exposure and clearance of HBV infection
Chronic infection
Exposure, false positive or chronic
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
Immune Clearance
HBV DNA
HBeAg+
Immune Control
(Nonreplicative)
HBeAg-
HBsAg+
HBeAb+
HBsAg- HBsAb+
ALT
5-30 Yrs
Mos-Yrs
Infection
Yim HJ, et al. Hepatology. 2006;43:S173-S181.
Mos-Yrs
Natural History of Chronic HBV Infection
Immunotolerance
Immune Clearance
HBV DNA
Immune Control
(Nonreplicative)
Most Oncology Patients
 Normal ALT
 Low/undetectable HBV DNA
 HBsAg+ and HBeAg or HBsAg-, anti-HBc+
HBeAg+
HBeAg-
HBsAg+
HBeAb+
HBsAg- HBsAb+
ALT
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
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.
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+
HBeAg-
HBeAb+
HBeAg+
Immunotolerance
Immune Clearance
HBV DNA
ALT
5-30 Yrs
Mos-Yrs
Infection
Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.
Mos-Yrs
HBV Reactivation
HBeAg+
HBeAg-
Immunotolerance
Immune Clearance
HBeAb+
HBeAg+
Immune Suppression
HBV DNA
ALT
5-30 Yrs
Mos-Yrs
Infection
Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.
Mos-Yrs
HBV Reactivation
HBeAg+
HBeAg-
Immunotolerance
Immune Clearance
HBeAb+
HBeAg+
Immune Suppression
HBV DNA
ALT
5-30 Yrs
Mos-Yrs
Infection
Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.
Mos-Yrs
Immune Reconstitution
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
Agents
Corticosteroids
Dexamethasone, methylprednisolone, prednisolone
Antitumor antibiotics
Actinomycin D, bleomycin, daunorubicin, doxorubicin,
epirubicin, mitomycin-C
Plant alkaloids
Alkylating agents
Antimetabolites
Vinblastine, vincristine
Carboplatin, chlorambucil, cisplatin, cyclophosphamide,
ifosfamide
Azauridine, cytarabine, fluouracil, gemcitabine,
mercaptopurine, methotrexate, thioguanine
Monoclonal antibodies
Others
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
HBsAg Patients (%)
100
80
60
48
40
22
20
4
4
0
HBV
Jaundice
Nonfatal
Reactivation
Liver Failure
Lok AS, et al. Gastroenterology. 1991;100:182-188.
Death
Risk Factors for HBV Reactivation
 Malignancy
 HBV DNA
– NHL: 40% to 58% of
HBsAg positive
– HBV DNA > 3 × 105
copies/mL
– Breast cancer: up to 41%
of HBsAg positive
– Elevated if HBeAg
positive
 Chemotherapy
– Prednisone,
anthracyclines, rituximab
increased risk
– “Potency of
immunosuppression”
Yeo W, et al. Hepatology. 2006;43:209-220.
 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)
ACE
PACE
HBsAg Patients (%)
100
80
73*
68
60
40
20
46
44*
38
*P < .05
28**
35
36
13
4
0
HBV
ALT
Reactivation > 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?
HBV Screening (%)
100
Chart Review
Self-Reported HBV Screening
Practices of 131 US Oncologists[1] of Actual Screening
(208 Pts at Single
Institution)[2]
80
62
60
40
24
20
14
14
All
Actual
Screening
Rate
0
None
High Risk
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.
Proportion of Oncologists (%)
Is Screening Only of High-Risk
Populations Effective?
100
Knowledge About HBV Screening
Among Oncologists
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
Survival Free From Hepatitis
Due to HBV Reactivation

100
Pts at Risk, n
Preemptive LAM
On-demand LAM
Preemptive LAM
75
50
P = .002 by log-rank test
On-demand LAM
(if HBV DNA increased)
25
0
0
10
20
Wk
30
40
15
15
12
13
10
10
9
4
6
2
Lau GK, et al. Gastroenterology. 2003;125:1742-1749.
Value of Preemptive Antivirals
 HBsAg-positive patients with NHL treated with CHOP
randomized to “preemptive” vs “on-demand” lamivudine
HBsAg Patients (%)
100
On-demand group: start LAM if ALT > 1.5 x ULN
Preemptive group: start LAM on Day 1 of CHOP
80
60
48
36
40
20
0
20
8
8
0
0
HBV Reactivation HBV Reactivation HBV Reactivation
and Hepatitis Flare and ALT >10 x ULN
and Jaundice
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 HBsAgnegative 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
Proportion of
Anti-HBc Positive,
HBsAg-Negative
Patients (%)
– HBsAg-negative, anti-HBc–positive individuals treated with
CHOP or CHOP-R
40
CHOP (n = 25)
CHOP-R (n = 21)
30
24
20
10
5
0
0
HBV Reverse
Seroconversion
0
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 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
Very low HBV DNA
Low HBV DNA
High HBV DNA
Lamivudine adequate
Lamivudine adequate
Tenofovir or Entecavir
HBV DNA
 Undetectable
 < 2000 IU/mL
 ≥ 2000 IU/mL
**If observation is chosen, monitor liver tests, HBsAg and HBV DNA q1-3 months