hepatitis b management in hematopoietic cell ......5 hbsag=hepatitis b surface antigen...

Hepatitis B Management in Hematopoietic Cell

Transplantation (HCT)

Aseala Abousaud, PharmD, BCOP

Clinical Pharmacy Oncology Specialist

Emory Healthcare, Atlanta, GA

Disclosures

• I will be discussing off-label (non-FDA approved) use of medication(s) in hepatitis B management in HCT patients

• I have nothing to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation.

2

Learning Objectives

• Describe prevention strategies and monitoring parameters for hepatitis B in HCT

• Identify potential management options for hepatitis B prophylaxis, reactivity, and new infection in high risk HCT patients

3

Definitions

• Hepatitis B virus (HBV) naïve —No exposure to hepatitis B

• Acute HBV infection—First infected or new infection

• Chronic HBV infection —Liver inflammation due to prolonged infection with HBV

• HBV reactivation (HBVr)—Inactive or resolved HBV infection that resurfaced

4

Terrault NA, et al. Hepatology. 2018;67(4);1560–1599.

Lampertico P, et al. J Hepatol. 2017;67(2):370–398.

Hepatitis B Virus (HBV) Epidemiology

Cumulative rate of reactivation within 2

years after HCT 6.3% to 21.7%

Incidence of reactivation in

resolved HBV ranges from 2.6% to 86%

Reactivation occurs on average between

10 to 48 months post-HCT

Hepatitis B surface antigen (HBsAg)

positive incidence of reactivation > 60%

HBsAg negative and hepatitis B core

antibody (HBcAb) positive incidence of reactivation 3 to 43%

5

HBsAg=Hepatitis B surface antigen HBcAb=Hepatitis B core antibody

Lee HL, et al. Digestive Diseases and Sciences. 2019;64:2992–3000.

Kato O, et al. British Journal of Haematology. 2019;186:e163–e225.

Sarmati L, et al. Clin Microbiol Infect. 2017;23:935.

Siyahian MS, et al. Biol Blood Marrow Transplant. 2018; 24(7):1483–1489.

Pathophysiology of HBV

DNA=deoxyribonucleic acid6

Liang, TJ. Hepatology. 2009;49(5):S13-S21.

HBsAg

HBcAg

HBeAg

Partially double-stranded DNA

DNA polymerase

Hepadnaviridae family

• Hepatitis B surface antigen (HBsAg)—Located on the surface of the virus

membrane

• Hepatitis B core antigen (HBcAg)—Intracellular antigen (nucleocapsid)

• Hepatitis B e antigen (HBeAg)—Small polypeptide in free form

• HBV DNA (viral load)

Hepatitis B Serologic Testing

HBsAg

• A protein on the surface

• High levels in the serum during acute or chronic infections

• Indicates patient is infectious

• Used to make the hepatitis B vaccine

Hepatitis B surface antibody (anti-HBs)

• Antibody made against the HBsAg

• Indicates recovery from infection and relative immunity

• Sign of a successful vaccination

HBcAb

• Antibody made against the core antigen

• Positive at the onset of acute hepatitis B

• Indicates previous or current infection

HBV DNA

• DNA fragments detected

• Used as a prognostic factor, defines phase of chronic hepatitis B, indicator for treatment, and assesses efficacy of antiviral treatment

7Centers for Disease Control and Prevention, Hepatitis B information for health professionals: Interpretation of hepatitis B serologic test results.

Appropriations: https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf. Accessed November 21, 2019.

HBV Replication Process

RNA=ribonucleic acid8

Liang, TJ. Hepatology. 2009;49(5):S13-S21.

Attachment

• Entry into cell via endocytosis

Penetration

• Merges with hepatocyte’s membrane and releases DNA and proteins into the cytoplasm

Uncoating

• Core proteins separate from partially double-stranded DNA and convert to covalently closed circular DNA (cccDNA)

• cccDNA is used for transcription of four messenger RNAs (mRNAs)

Replication

• One of the mRNA strands makes new copies of genetic material

Assembly

• The four mRNA form virionsthat are cycled to continue to produce virions

Release

• Reverse transcriptase synthesizes DNA and then releases from the cell membrane

HBV Infection

Virus infects hepatocytes

Antigen-presenting cells present viral and surface antigens to CD8+ and CD4+ T-cells

CD8+ T-cells release cytokines and destroy hepatocytes

Initial increase in viral replication and HBV DNA levels

Following the decrease in HBV DNA levels, ALT rises

ALT=alanine transaminaseCD=cluster of differentiation

IgM=Immunoglobulin M 9

Chisari FV, et al. Pathol Biol (Paris). 2010;58(4):258–266.

Krajden M, et al. Can J Infect Dis Med Microbiol. 2005;16(2): 65–72.

Moses SE, et al. Expert Review of Anti-infective Therapy. 2011;9:891–899.

HBsAg

positive

HBV DNA viral load

IgM HBcAb

positive

HBV Infection Continued

CD4+ memory T-cells mediate clonal expansion of B-cells

Secretion of antibodies to hepatitis B surface antigen

Decrease in ALT and detection of HBV specific antibodies Resolution

10

Chisari FV, et al. Pathol Biol (Paris). 2010;58(4):258–266.

Krajden M, et al. Can J Infect Dis Med Microbiol. 2005;16(2): 65–72.

anti-HBs

positive

IgG HBcAb

positive

HBV Lab Interpretation

*Low viral load is defined as HBV DNA of < 104 copies/mL

** High viral load is defined as HBV DNA ≥ 104 copies/mL

11

Centers for Disease Control and Prevention, Hepatitis B information for health professionals: Interpretation of

hepatitis B serologic test results. Appropriations: https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf.

Accessed November 21, 2019.

Belopolskaya et al. Ann Gastroenterol. 2015; 28(3): 379–384.

Tests Results Interpretation

HBsAg Positive Chronically infected

(low viral load*)HBcAb Positive

Acute infection

(high viral load**)Anti-HBs Negative

HBsAg Negative

Natural infectionHBcAb Positive

Anti-HBs Positive

HBsAg NegativeHepatitis B vaccination

(anti-HBs titer > 10 IU/L immune)HBcAb Negative

Anti-HBs Positive

HBsAg Negative1. Resolved infection

2. Resolving acute infectionHBcAb Positive

Anti-HBs Negative

ARS Question 1:

• The lab results from the below hepatitis B panel are most consistent with which of the following?

A. Acute hepatitis B infection

B. HBV naïve

C. Administration of the hepatitis B vaccine

D. Prior exposure to hepatitis B that has resolved

12

Hepatitis B surface antigen (HBsAg) Negative

Hepatitis B core antibody (HBcAb) Positive

Hepatitis B surface antibody (anti-HBs) Positive

High Risk Patients for Hepatitis B reactivation (HBVr) in HCT

HIV=human immunodeficiency virusalloHCT=allogeneic HCT

13

Siyahian A, et al. Biol Blood Marrow Transplant. 2018;24(7):1483–1489.

Locasciulli A, et al. Mediterr J Hematol Infect Dis. 2009;1(13):e2009016.

• HBsAg positive patients (highest risk)

• High serum HBV-DNA viral load

• Immunosuppressive medications: Fludarabine, rituximab, anti-thymocyteglobulin(ATG), alemtuzumab, tumor necrosis factor (TNF) blockers

• HIV positive patients who receive transplant from HBV-naïve donors

• Lymphoma patients

• alloHCT patients—Chronic graft versus host disease (GVHD) high doses of corticosteroids

HBVr Prophylaxis Recommendations

NCCN=National Comprehensive Cancer NetworkAASLD=American Association for the Study of Liver Disease

EASL=European Association for the Study of the LiverIDSA=Infectious Disease Society of America

CIBMTR=Center for International Blood and Marrow Transplant Research14


NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention

and Treatment of Cancer-related Infections V.1.2019.



NCCN 2019 AASLD 2018 EASL 2017 IDSA CIBMTR

HBsAg positive HBsAg positive HBsAg positive HBsAg positive HBsAg positive

HBV DNA positive - - HBV DNA positive HBV DNA positive

HBsAg negative

HBcAb positive

HBsAg negative

HBcAb positive

HBsAg negative

HBcAb positiveHBcAb positive HBcAb positive

If HBsAg positive = Antiviral prophylaxis

If HBcAb positive regardless of anti-HBs status= Antiviral prophylaxis

Prevention of HBVr Monitoring Recommendations

Anti-HBV=antiviral hepatitis B virusLFT=Liver function test

15


NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-related Infections V.1.2019.



NCCN 2019 AASLD 2018 EASL 2017

Labs HBV DNA HBV DNALFT

HBV DNA

Patients

HBsAg positive

HBcAb positive and

increasing viral load

HBV DNA positive

HBsAg negative and

HBcAb positive

On anti-HBV therapy

FrequencyAt least 6 to 12 months

post-HCT and during GVHD

Every 1 to 3 months up to

12 months after completion

of anti-HBV therapy

Every 3 to 6 months during

prophylaxis and at least for

12 months after completion

of anti-HBV therapy

Antiviral Prophylaxis Options

Lamivudine (LAM) – historical

Entecavir (ETV)

Tenofovir disoproxil fumarate (TDF)

Tenofovir alafenamide fumarate (TAF)

16

HBVr Prophylaxis: Lamivudine

yo=years old17


Cerva C, et al. Bone marrow transplantation. 2016;51:S199.

Gupta A, et al. Hematol Oncol. 2016;34(3):140–146.

Giaccone L, et al. Biol Blood Marrow Transplant. 2010;16(6):809–817.

Topcuoglu P, et al. Biology of Blood and Marrow Transplantation. 2010;16(2):S288.

Moses SE, et al. J Med Virol. 2006;78(12):1560–1563.

Lau GK, et al. Hepatology. 2002;36(3):702–709.

Study High risk (HR)* Intervention Results

Zappulo 2018 50 Lamivudine 100 mg during treatment 0/50 HBVr (0%)

Cerva 2016 45 Lamivudine 100 mg x 30 months 2/45 HBVr (4.4%)

Gupta 2016 7Lamivudine 100 mg or 3 mg/kg/day

(<12 yo) x 6 months0/7 HBVr (0%)

Giaccone 2010 30 Lamivudine 100 mg x 40 months 3/30 HBVr (10%)

Topcuoglu 2010 23 Lamivudine 100 mg x 6-12 months 4/23 HBVr (39%)

Moses 2006 15 Lamivudine 100 mg x 6 months 3/15 HBVr (20%)

Lau 2002 20 Lamivudine 100 mg x 13 months 1/20 HBVr (5%)

*HR = HBsAg positive only or HBV DNA quantitative positive (greater than 2000 IU/ml) only, HBsAg positive but HBV DNA quantitative negative

(less than 2000 IU/ml), HBcAb positive, HBcAb positive and Anti-HBs positive, prior HBV vaccination status unknown.

HBVr Prophylaxis: Entecavir

IU=International units18


Shang J, et al. Bone marrow transplantation. 2016;51(4):581–586.

Liao YP, et al. World J Gastroenterol. 2015;21(14):4284–4292.

Aoki J, et al. Springerplus. 2014;3:450.

Tsuji M, et al. Blood. 2012;120(21).

Study HR* Intervention Results

Shang 201688

75

Lamivudine 100 mg vs

Entecavir 0.5 mg x 24 months

Lamivudine

28/88 HBVr (31.81%)

Entecavir

2/75 HBVr (2.67%)

Liao 2015 57 Entecavir 0.5 mg x 12 months 1/57 HBVr (1.57%)

Aoki 2014 4 Entecavir 0.5 mg x 12.5 months 0/4 HBVr (0%)

Tsuji 2012 158Lamivudine 100 mg (12 patients)

Entecavir 0.5 mg (146 patients) x indefinite 0/158 HBVr (0%)

*HR = HBsAg positive only or HBV DNA quantitative positive (greater than 2000 IU/ml) only, HBsAg positive but HBV DNA quantitative negative

(less than 2000 IU/ml), HBcAb positive, HBcAb positive and Anti-HBs positive, prior HBV vaccination status unknown.

HBVr Prophylaxis: TDF and TAF

19


Zhang MY, et al. Expert Rev Anti Infect Ther. 2017;15(5):503–513.

• There are no studies in HCT patients using TDF or TAF as prophylaxis for HBVr

• Zhang and colleagues —Meta-analysis comparing five antivirals for prophylaxis in HBVr

—Patients were immunosuppressed with hematological malignancies

—Results:

• Found superior efficacy for ETV and TDF versus LAM

HBV Antiviral Prophylaxis Duration Recommendation

Autologous HCT

Continue prophylaxis for at least 6 to 12 months post HCT

Allogeneic HCT

Continue prophylaxis for 6 to 12 months after completion of

immunosuppression

Recommend to continue prophylaxis

if HBV DNA is positive or HBsAg

positive

20


NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and

Treatment of Cancer-related Infections V.1.2019.



HBV Antiviral Medication

Entecavir [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; December 2018.

Chen Fw, et al. Liver Int. 2013;33(8):1203-1210.

Tenofovir [prescribing information]. Foster City, CA: Gilead Sciences Inc; April 2019.


Tenofovir alafenamide [product monograph]. Mississauga, Ontario, Canada: Gilead Sciences Canada, Inc; May 2019.21

Drugs EntecavirTenofovir disoproxil

fumarate (TDF)

Tenofovir alafenamide

fumarate (TAF)

Mechanism of

action

Nucleoside reverse

transcriptase inhibitor

Nucleotide reverse


Nucleotide reverse


Dose0.5 mg PO daily

1 mg PO daily*300 mg PO daily 25 mg PO daily

Administration

Empty stomach

2 hours before or after a

meal

Without regard to meals With food

*Prior lamivudine-refractory, lamivudine-resistant viremia, or decompensated liver disease

HBV Antiviral Medication Continued

Entecavir [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; December 2018.

Chen Fw, et al. Liver Int. 2013;33(8):1203-1210.

Tenofovir [prescribing information]. Foster City, CA: Gilead Sciences Inc; April 2019.


Tenofovir alafenamide [product monograph]. Mississauga, Ontario, Canada: Gilead Sciences Canada, Inc; May 2019..22

Drugs Entecavir Tenofovir disoproxil

fumarate (TDF)

Tenofovir alafenamide

fumarate (TAF)

Adverse

effects

Lactic acidosis,

hyperglycemia,

hematuria

Lactic acidosis,

decreased BMD,

renal impairment,

hypercholesterolemia

Hypercholesterolemia

Dose

adjustment

Renal impairment

CrCl < 50 mL/min

Renal impairment

CrCl < 50 mL/min

Use not recommended in

CrCl < 15 ml/min

Clinical

pearls

Liquid formulation:

bioequivalent with tablets

Powder formulation

Limited data in HCT

Monitor BMD

Preferred agent in

renal dysfunction

Limited data in HCT

Decreased bone toxicity

CrCl=creatinine clearance

BMD=Bone mineral density

HBV Donor Selection Consideration

23Tomblyn M, et al. Biology of Blood and Marrow Transplantation. 2009;15:1143–1238.

Prior exposure to HBVHBcAb positive

(natural immunity)Antiviral prophylaxis

HBV naïve anti-HBs positive

(vaccinated immunity)

No prophylaxis

Vaccinate prior to HCT if possible

HBV vaccinated anti-HBs positive

(vaccinated immunity)No prophylaxis

Patient Preferred Donor Recommendation

HBV Donor Selection Consideration (Continued)

24Tomblyn M, et al. Biology of Blood and Marrow Transplantation. 2009;15:1143–1238.

HBV vaccinated HBcAb positive

(natural immunity)

HBV DNA negative and

stem cell collection negative

No prophylaxis Monitor ALT first

6 months

HBV vaccinated or HBV naïve

HBsAg positive

DNA positive

Treat donor at least 4 weeks or until HBV DNA

negative

Antiviral prophylaxis

HBV vaccinated HBcAb positive

(natural immunity)

Stem cell collection positive

Antiviral prophylaxis

Patient Donor Recommendation

HBV Vaccination

• Hepatitis B immunization should be done for all HBV-naïve patients—Recommendation for both patient and donor

• Isolated HBcAb positive patient—Recommended to receive vaccination prior to transplant if possible

• Post-HCT vaccination once immune recovery ~ 6 – 12 months

25


Tomblyn M, et al. Biology of Blood and Marrow Transplantation. 2009;15:1143–1238.


Liang R. Blood. 2009;113:3147–3153.


HBV Vaccines

Hepatitis B vaccine - recombinant

• 3 doses over 6 months

• 0, 1, and 6 months

• Intramuscular

• Aluminum adjuvant

• Extensive safety data

• Cost ~$190

• Immunocompromised adults: 4 doses at double the dose

• 0, 1, 2, and 6 months

Hepatitis B vaccine –recombinant, adjuvanted

• FDA approved November 2017

• 2 doses separated by 1 month

• 0 and 1 month

• Intramuscular

• Novel immunostimulatory adjuvant

• Cost ~$230

• Not studied in immunocompromised patients

Schillie S, et al. MMWR Recomm Rep. 2018;67:1.

Stephenne J, et al. Vaccine.1990;8:S69.

Jackson S, et al. Vaccine. 2018;36:668-674.

Lampertico P, et al. J Hepatol. 2017;67(2):370–398.26

ARS Question 2:

• DH is a 54 year old African American who is being worked up for an allogeneic transplant. Based on this hepatitis panel, would you recommend antiviral prophylaxis?

A. No antiviral prophylaxis, because he is HBsAg negative

B. Yes antiviral prophylaxis, because he has an active hepatitis B infection

C. Yes antiviral prophylaxis, because he will be at risk for reactivation

D. No antiviral prophylaxis, because he has a chronic hepatitis B infection

27

Hepatitis B surface antigen (HBsAg) Negative

Hepatitis B core antibody (HBcAb) Positive

Hepatitis B surface antibody (anti-HBs) Positive

HBV New Infection: Diagnosis

• Criteria for diagnosis —Based on ALT and DNA levels

• Differential diagnosis—Veno-occlusive disease

—GVHD

• Consult hepatology

• Treatment—ETV, TDF, or TAF

• HBsAg positive infectious—Seroconvert = HBsAg negative HBsAg positive

• IgM HBcAb positive—Onset of acute infection

—Best marker for acute infection

• HBeAg—Viral replication

—Risk of passing infection


Liang R. Blood. 2009;113:3147–3153.

Tomblyn M, et al. Biology of Blood and Marrow Transplantation. 2009;15:1143–1238

Ramos CA, et al. Biology of Blood and Marrow Transplantation. 2010;16:686–694.28

HBVr Treatment: ETV, TDF, and TAF

29

Woo G, et al. Gastroenterology 2010; 139: 1218–1229.

Hilgendorf I, et al. Blood Marrow Transplant. 2011;46(9):1274–1275.

• Woo and colleagues —Bayesian meta-analysis TDF and ENT found to be most potent antivirals

—Two patients who had resolved HBV infection with HBVr post-HCT due to immunosuppression

• Case report (letter to the editor)—cGVHD in previously resolved HBV who had reactivation and treated with TDF

HBV New Infection Treatment Duration Recommendation

Autologous HCT

Continue treatment for at least 6 months post HCT

Allogeneic HCT

Continue treatment for 6 months after completion of

immunosuppression

Recommend to monitor HBV DNA and liver enzymes for

at least 3 months post antiviral/immunosuppression

treatment

30


Liang R, et al. Blood. 2009;113:3147–3153.

Tomblyn M, et al. Biology of Blood and Marrow Transplantation. 2009;15:1143–1238.

Ramos CA, et al. Biology of Blood and Marrow Transplantation. 2010;16:686–694.

Summary

• HCT patients are at risk for HBV infections due to prolonged immunosuppression

• HBV complication in HCT can be avoided through proper screening and initiation of antiviral prophylaxis

• Patients with HBsAg positivity are at highest risk for HBVr

• Routine monitoring should be performed though recommendations vary on duration and frequency

• Pharmacists play a role in ensuring proper management in initiation of antiviral treatment and monitoring parameters

31

Recommended references

• Siyahian A, et al. Prophylaxis for Hepatitis B Virus Reactivation after Allogeneic Stem Cell Transplantation in the Era of Drug Resistance and Newer Antivirals: A Systematic Review and Meta-Analysis. Biol Blood Marrow Transplant. 2018;24(7):1483–1489.

• NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-related Infections V.1.2019.

• Tomblyn, M., et al. Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplantation Recipients: A Global Perspective. Biology of Blood and Marrow Transplantation. 2009;15:1143-1238.

• Moses, S.E., Lim, Z. & Zuckerman, M.A. Hepatitis B virus infection: pathogenesis, reactivation and management in hematopoietic stem cell transplant recipients. Expert Review of Anti-infective Therapy. 2011; 9:891-899.

• Liang, R. How I treat and monitor viral hepatitis B infection in patients receiving intensive immunosuppressive therapies or undergoing hematopoietic stem cell transplantation. Blood. 2009;113;3147-3153.

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hepatitis b management in hematopoietic cell ......5 hbsag=hepatitis b surface antigen...

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