hepatitis b infection: an under- recognized problem in oncology atif zaman md mph professor of...
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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.
In accord with ORS.41675 related to QA, Teaching & Supervision of Medical Staff Physicians
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
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
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
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
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
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
Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.
Along Comes Immune Suppression
Immune control can be lost
Immune-mediated liver damage with immune reconstitution
HIVSteroidsChemotxT cell
T cell
T cell
cccDNA
Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.
Along Comes Immune Suppression
Immune control can be lost
Immune-mediated liver damage with immune reconstitution
HIVSteroidsChemotxT cell
T cell
T cell
cccDNA
Werle-Lapostolle B, et al. Gastroenterology. 2004;126:1750-1758.
HBV Reactivation
5-30 Yrs Mos-YrsInfection
ImmunotoleranceImmune Clearance
HBeAg+ HBeAg- HBeAb+
Mos-Yrs
ALT
HBV DNA
HBeAg+
Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.
HBV Reactivation
5-30 Yrs Mos-YrsInfection
ImmunotoleranceImmune Clearance
HBeAg+ HBeAg- HBeAb+
Mos-Yrs
ALT
HBV DNA
HBeAg+
Immune Suppression
Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.
HBV Reactivation
Infection
ImmunotoleranceImmune Clearance
HBeAg+ HBeAg- HBeAb+
ALT
HBV DNA
HBeAg+
Immune Suppression Immune Reconstitution
Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.
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
Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.
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
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
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
Yeo W, et al. Hepatology. 2006;43:209-220.
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
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.
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.
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.
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