Management of Hepatitis B reactivationregist2.virology-education.com/.../TokyoHEP/09_tanaka.pdfManagement of Hepatitis B reactivation Nagoya City University Graduate School of Medical

Management of Hepatitis B

reactivation

Nagoya City University Graduate School

of Medical Sciences

Yasuhito Tanaka

TOKYO HEP CLINICAL FORUM

Oct 28-29, 2019

Tokyo

HBV reactivation after immunosuppressive therapy

HBV-resolved

Contents

1. Risk of HBV reactivation in cancer patients

following systemic chemotherapy (Cx)

2. Screening and risk-adopted management to

prevent HBV reactivation following Cx

3. HBV reactivation with cancer immunotherapy/

molecular targeting therapy

Risk of HBV Reactivation Following

Systemic Cx Depends on the Balance

Replication

of the virus

Immune

response of

the host

Molecular targeting drugs beyond rituximab

could cause de novo hepatitis B

Drug

Everolimus（AFINITOR®）

Mogamulizumab（POTELIGIO®）

Ruxolitinibルキソリチニブ

（JAKAVI® ）

Nivolumab（OPDIVO® ）

Target diseases

RCC

Breast cancer

Angiomyolipoma

PanNEN SEGA

ATL

Cutaneous T-cell

lymphomaSolid cancers ?

Myelofibrosis

Polycythemia vera

Melanoma

non-small cell LK

RCC Gastric cancer

Approved

Jan, 2010

May 2012

July 2014

July 2014

Mechanism

mTOR inhibitor

Anti-CCR4

antibody

JAK1/2 inhibitor

PD-1 antagonist

Drug

Everolimus（AFINITOR®）

Mogamulizumab

（POTELIGIO®）

Ruxolitinib（JAKAVI® ）

Nivolumab（OPDIVO® ）

Target diseases

RCC

Breast cancer

Angiomyolipoma

PanNEN SEGA

ATL

Cutaneous T-cell

lymphomaSolid cancers ?

Myelofibrosis

Polycythemia vera

Melanoma NSCLC

RCC Gastric cancer

Approved

Jan, 2010

May 2012

July 2014

July 2014

Mechanism

mTOR inhibitor

Anti-CCR4

antibody

JAK1/2 inhibitor

PD-1 antagonist

Molecular targeting drugs beyond rituximab

could cause de novo hepatitis B

cancer

novel cancer vaccine

Specific CTL induction

cancer&

environment cells

CCR4 ligandproduction

Treg (CCR4+) accumulation

MogamulizumabAnti-CCR4 mAb

treatment

The next-generation comprehensive cancer immunotherapy

CTL inductionkilled cancer cells

ADCC activation

Mogamulizumab depletes CCR4(+) Tregs, resulting in CTL induction.

Ifuku H et al, Hepatol Res. 2015 一部改変

HBsAg negative at baseline

Anti-HBcAbpositive Pre-administration checking

for mogamulizumab:HBV reactivation occurred.

HBsAg positive, HBV-DNA> 9.1, No liver damage

72 year old male ATL lymphoma type

Mogamulizumab single dose administration start while entecavir

prophylaxis administration

Fulminant hepatitis by Mogamulizumab injection

Fulminant hepatitis by Mogamulizumab injectionIfuku H et al, Hepatol Res. 2015 一部改変

Mogamilizumab Days after Mogamilizumab injection

（1回目）（2回目）（3回目） 24 26 27 28 30 32 34

Entecavir

AST 39 32 91 4150 4910 5310 3700 2290 1310 550

ALT 25 20 69 2410 2760 3080 2410 1750 1270 780

T-Bil 1.08 1.01 0.99 6.01 11.07 13.98 16.56 21.6 26.56 32.2

72 year old male ATL lymphoma type

✓ 24 days after Mogamulizumab injection caused fulminant hepatitis, even though he started entecavir at baseline.

✓ It is important to reduce HBV-DNA as long as possible before Mogamulizumab injection.

Contents







Risk Classification for HBV Reactivation after

Immunosuppressive Therapy

HBV Status

Immunosuppression

Systemic Cx Allo-SCT

HBsAg(+)

Resolved

HBsAg(-)

anti-HBc(+)

and/or

anti-HBs(+)

All marker

negative

Rituximab +

Steroid-containing Cx

High risk

14-20%

Low risk

<1-3%

Very high risk

＞50%

High risk

24-53%

High risk10-24% (retrospective)

9-30% (prospective)

Modified from Kusumoto S et al.: Int J Hematol 2009;90:13-23

No risk

Very high risk

59-80%

The risk of HBV reactivation varies according to the HBV infection status before chemotherapy, but also according to the degree of immunosuppression.


Immunosuppressive TherapyHBV Infection Status

Immunosuppression


HBsAg(+)

HBsAg(-)

anti-HBc(+)

and/or

anti-HBs(+)

All marker

negative

Rituximab +


High risk

14-20%

Low risk

<1-3%

Very high risk

＞50%

High risk

24-53%


9-30% (prospective)

(Modified from Kusumoto S et al.: Int J Hematol 2009;90:13-23)

No risk

Very high risk

59-80%

Focus the incidence of HBV reactivation in HBsAg-positive patients with systemic chemotherapy

HBV reactivation in HBsAg-positive Pts

with solid tumors following Cx by meta-analysis

Modified from Paul S et al, Ann Intern Med. 2016; 164: 30.

Definition:

HBV reactivation was

defined by a greater than

10-fold increase in HBV DNA

levels from baseline or an

absolute increase greater

than 10^5 copies/mL.

Total prevalence of HBV reactivation

：198/977, 20% (95%CI: 18-23)

HBV reactivation in HBsAg-positive Pts

with major solid tumors following Cx by meta-analysis

Modified from Paul S et al, Ann Intern Med. 2016; 164: 30.

Tumor SubtypeEvents/Total,

n/N

Absolute risk

for HBVR*95%CI

GI 26/164 16% 10-21%

Breast 104/491 21% 18-25%

Lung 43/217 20% 15-25%

Head and neck 11/40 28% 14-41%

Other 6/46 13% 3-23%

*HBVR, HBV reactivation was defined by a greater than 10-fold increase in HBV

DNA levels from baseline or an absolute increase greater than 10^5 copies/mL


Immunosuppressive TherapyHBV Infection Status

Immunosuppression


HBsAg(+)

Resolved

HBsAg(-)

anti-HBc(+)

and/or

anti-HBs(+)

All marker

negative

Rituximab +


High risk

14-20%

Low risk

<1-3%

Very high risk

＞50%

High risk

24-53%


9-30% (prospective)

Modified from Kusumoto S et al.: Int J Hematol 2009;90:13-23

No risk

Very high risk

59-80%

Retrospective analysis for HBV reactivation

in HBsAg-negative patients with solid tumors

➢ To estimate the risk of HBV reactivation in HBsAg-

negative patients with solid tumors following systemic

chemotherapy, this retrospective study was conducted.

➢ In this study, 1,420 HBsAg-negative patients with solid

tumors who treated with systemic chemotherapy in

Nagoya City University Hospital between April 2012

and March 2015 were enrolled.

➢ HBV reactivation was defined as reappearance of

HBsAg or an elevation in HBV DNA levels of 2.1 log

copies/mL or more.

Kuroda J et al, The 54th Annual Meeting of Japan Society of Clinical Onclogy, WS83-4

Characteristics of HBsAg-negative patients

with solid tumors in our hospital

Kuroda J et al, The 54th Annual Meeting of Japan Society of Clinical Onclogy, WS83-4

N (%)

Total number of

patients1,420

Gender

Male 741

Female 679

Tumor types N

Lung cancer 278

Breast cancer 217

Colon cancer 181

Ovarian/uterus cancer 133

Gastric cancer 128

Liver/gallbladder/pancreatic

cancer122

Head and neck cancer 90

Urological cancer 85

Esophageal cancer 78

Bone/soft tissue cancer 33

Other 75

Follow-up Days

Median 617

Range 0-1,589

Age years

Median 65

Range 0-97

Nagoya City University Hospital

Incidence of HBV reactivation during chemotherapy

Kuroda J et al, The 54th Annual Meeting of

Japan Society of Clinical Onclogy, WS83-4 HBsAg-negative

N=1,420

anti-HBc-positive

and/or

anti-HBs-positive

n=216 (15.2%)

HBV reactivation

n=2

(1%)

Anti-HBc Anti-HBs N

(+) (+) 122

(+) (-) 35

(+) NA 2

(-) (+) 56

(-) NA 1

The 2 (6%) of 35 anti-HBc-positive but

anti-HBs-negative patients had HBV

reactivation, but none of 122 patients

with both anti-HBc and anti-HBs.

The 2 patients were positive for only anti-HBc, but negative for anti-HBs.

• Case1: 63 yrs, male, Lung cancer; peak HBV DNA:2.7 log copies/mL

• Case2: 73 yrs, male, Lung cancer; peak HBV DNA:2.1 log copies/mL

HBV-resolved

Contents







Antiviral prophylaxis: an antiviral drug is given

before initiating immunosuppressive therapy

Regular HBV DNA monitoring-guided

preemptive antiviral therapy: an antiviral drug is

given when HBV DNA in the blood is detected

Management of HBV Reactivation following Cx

To prevent HBV reactivation, the current

recommendable options include:

Screening test: HBsAg, anti-HBc, anti-HBs

Risk group 1:

HBsAg (+)

HBsAg(-)

anti-HBc(+) and/or anti-HBs(+)i

HBV DNA levels measurement

Risk group 2:

HBsAg (-) but HBV DNA (+)(occult HBV infection)

(+)

Risk group 3:

HBsAg (-), HBV DNA (-)

anti-HBc (+) and/or anti-HBs (+)(resolved HBV infection)

(-)

No risk:

All marker(-)

Management of HBV Reactivation Following Cx

Antiviral prophylaxis Regular HBV DNA monitoring-

guided preemptive antiviral Tx

Kusumoto S and Tobinai K. Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):576-83.

Antiviral prophylaxis was recommended to

prevent HBV reactivation in HBsAg-positive and/or HBV-DNA positive patients.

Screening test: HBsAg, anti-HBc, anti-HBs

Risk group 1:

HBsAg (+)

HBsAg(-)

anti-HBc(+) and/or anti-HBs(+)i

HBV DNA levels measurement

Risk group 2:

HBsAg (-) but HBV DNA (+)(occult HBV infection)

(+)

Risk group 3:

HBsAg (-), HBV DNA (-)

anti-HBc (+) and/or anti-HBs (+)(resolved HBV infection)

(-)

No risk:

All marker(-)

Management of HBV Reactivation After Anti-B-Cell Tx

Antiviral prophylaxis Regular HBV DNA monitoring-

guided preemptive antiviral Tx

Kusumoto S and Tobinai K. Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):576-83.

Prospective studies for preventing HBV reactivation

in B-cell lymphoma patients with resolved HBV infectionPrincipal

investigator

Subjects （HBV status/type

and treatment of lymphoma）

Sample

size

Study design Start date

Kusumoto S

(Japan)

Anti-HBc (+) and/or

anti-HBs (+), B-NHL

Rituximab plus

steroids

321 HBV-DNA monitoring

single arm, 68 institutions

Aug. 2008

1)

Liu TW

(Taiwan)

Anti-HBc (+),

DLBCL or FL

R-CHOP 150 HBV-DNA monitoring

single arm, 14 institutions

Jun. 2009

2)

Ji D

(China)

Anti-HBc (+),

DLBCL

R-CHOP 110 HBV-DNA monitoring

single arm, one institution

Oct. 2010

3)

Yuen MF

(Hong Kong)

Anti-HBc (+),

B-cell lymphoma,

CLL

Rituximab-

containing

chemotherpay

70 HBV-DNA monitoring

single arm, one institution

Dec. 2011

4)

Huang YH

(Taiwan)

Anti-HBc (+),

B-cell lymphoma

NA 90 prophylaxis vs. therapeutic

RCT, single institution

Apr. 2009

5)

Zhu J and

Song Y

(China)

Anti-HBc (+),

lymphoma

Chemotherapy 190 prophylaxis vs. therapeutic

RCT, 13 institutions

Jan. 2013

6)

1) UMIN000001299, 2) NCT00931229, 3) NCT01210287, 4) NCT01502397, 5) NCT00926757, 6) NCT01765231

ID of Clinical Trial:

0.00

0.05

0.10

0.15

0.20

0.25

Prob

abil

ity

269 240 227 207 20 15 Number at risk

0 6 12 18 24 30Months after registration

12.2.1.-1 Probability of HBV reactivation_269_131031

The incidence of HBV reactivation at 1.5 year

was 8.3% (95% CI, 5.5-12.4)*

Median HBV-DNA follow-up time 561 days (range, 35-959)

Incidence of HBV reactivation (primary endpoint)

HBV reactivation:

median 97 days

（range：32-490）

*Pt #22 was excluded because HBV reactivation was confirmed by HBV DNA measurement not per-protocol.

Kusumoto S, et al. Clin Infect Dis. 2015; 61:719-29.

VariablesCrude

HR95% CI P Value

Adjusted

HR95% CI P Value

Age, per 10-y increase 2.2 1.2-4.0 0.010 1.4 0.7-2.9 0.404

Sex

Male

Female

3.2

1.0 (Ref.)

1.2-8.7 0.022 1.8

1.0 (Ref.)

0.6-5.2 0.289

Type of lymphoma

DLBCL

Non-DLBCL

3.5

1.0 (Ref.)

1.2-10.3 0.025 2.0

1.0 (Ref.)

0.6-5.2 0.289

Performance status (ECOG)

2

0 or 1

0.9

1.0 (Ref.)

0.1-6.9 0.943 - - -

International prognostic index

High-intermediate risk or high risk

Low risk or low-intermediate risk

1.3

1.0 (Ref.)

0.5-3.0 0.607 - - -

Type of regimen

R-CHOP

Other regimens

0.4

1.0 (Ref.)

0.2-1.2 0.093 0.5

1.0 (Ref.)

0.1-1.6 0.221

Anti-HBc

≥1.0 s/co

<1.0 s/co

1.8

1.0 (Ref.)

0.2-13.3 0.572 - - -

Anti-HBs

<10 mIU per milliliter

≥10 and <100 mIU per milliliter

≥100 mIU per milliliter

19.5

6.9

1.0 (Ref.)

4.3-88.9

1.5-31.4

<0.001

0.013

20.6

5.2

1.0 (Ref.)

3.9-105.8

1.0-25.7

<0.001

0.044

HBV DNA below quantification

Detected

Not detected

34.5

1.0 (Ref.)

12.2-97.3 <0.001 56.2

1.0 (Ref.)

15.3-207.0 <0.001

Risk factors for HBV reactivation Kusumoto S, et al. Clin Infect Dis. 2015; 61:719.

The multivariate analysis showed that 1) baseline HBs

antibody <10 mIU / mL, and 2) baseline HBV DNA signal

positive factors, significantly related to HBV reactivation.

Comparison of Prospective Studies on HBV DNA Monitoring-Guided

Preemptive Antiviral Therapy

Taiwan(Hsu C, et al.: Hepatology 2014*)

Japan(Kusumoto S, et al.: CID 2015**)

Number of pts n=150 n=275

Definition of HBV

reactivation (HBVR)

>10-fold increase in HBV

DNA than baseline

HBV DNA 1.8 log copies/mL,

or more

Cutoff values of HBV

DNA levels3.0 log copies/mL 1.8 log copies/mL

Intervals of HBV DNA Every 4 weeks Every 4 weeks

HBV reactivation 11% 8%

Severe hepatitis due

to HBVR7% (10/150) 0%

HBV-related death 0% 0%

*Hepatology 2014;59:2092-100. **Clin Infect Dis. 2015;61:719-29.

Severe hepatitis defined as ALT >10 fold of upper normal limit

Higher sensitive assay of HBV DNA is required to prevent hepatitis.

Because of higher cutoff values of HBV DNA (less sensitive), 7% of HBV-

resolved patients who received R-CHOP developed hepatitis B.

Summary for preventing hepatitis B

after Immunosuppressive therapy

HBV Infection Status

Immunosuppression


HBsAg(+)

Resolved

HBsAg(-)

anti-HBc(+)

and/or

anti-HBs(+)

All marker

negative

Rituximab +


High risk

14-20%

Low risk

<1-3%

Very high risk

＞50%

High risk

24-53%


9-30% (prospective)

Kusumoto S et al.: Int J Hematol 2009;90:13-23

No risk

Very high risk

59-80%

4Antiviral prophylaxis recommended

Regular HBV DNA monitoring-guided

preemptive antiviral therapy recommended

Mogamulizumab, Everolimus,

Bortezomib, Ruxolitinib

Introduction of HBsAg-based monitoring

HBV DNAmonitoring

HBsAg-HQmonitoring

Cost2,900 JYN

（26 USD）880 JYN

（8 USD）

Measurement time

3 hours 25 min

Sensitivity 20 IU/mL0.005 IU/mL

(DNA; 200 IU/mL）

Volume 650 μl 150 μl

Introduction of high-sensitive HBsAg-HQ enables rapid diagnosis.

CQ: How about cost-benefit of regular monitoring using HBV-DNA assay?

Summary for preventing hepatitis B

after Immunosuppressive therapy

HBV Infection Status

Immunosuppression


HBsAg(+)

Resolved

HBsAg(-)

anti-HBc(+)

and/or

anti-HBs(+)

All marker

negative

Rituximab +


High risk

14-20%

Low risk

<1-3%

Very high risk

＞50%

High risk

24-53%


9-30% (prospective)

Kusumoto S et al.: Int J Hematol 2009;90:13-23

No risk

Very high risk

59-80%

4Antiviral prophylaxis

Mogamulizumab, Everolimus,

Bortezomib, Ruxolitinib

High sensitive HBsAg measurement

is available for low risk group?

ALP labeled HBsAb

2nd reaction

AMPPD measuringchemiluminescent

1st reaction

denature

HBV particle

linearized HBsAg(“a” determinant)

inner epitope（28-80 a.a.）

HBsAb binding particle A（anti-”outer structural epitope” antibody conjugated）

HBsAb binding particle B（anti-”inner epitope” antibody conjugated）

Cut-off value (10-fold higher sensitivity)Lumipulse HBsAg-HQ assay: 0.005 IU/mLAbbott Architect HBsAg QT assay: 0.05 IU/ml

The principle of Lumipulse HBsAg-HQLinearized HBsAg after denature were detected using two monoclonal antibodies against outer structural epitope as determinant “a” and the internal epitope as a capture reagent.

HBsAg-HQ64

(19.5%)

21(6.4%)

HBcrAg48

(14.6%)

Detectable HBsAg-HQ and/or HBcrAg (FujiRebio) among CHB patients undetectable HBsAg by the conventional assay (Abbott Architect)

Detectable rates are 40% (133/329) ⇒ high prevalence of occult HBV

(Seto et al., Hepatol Int. 2012)

Case #2: ATL (56 years female, HBV-resolved patient) after allo-BMT

Anti-HBs （-）0.8

（-）0.7

（-）0.4

（-）0.7

（-）0.8

（-）2

100

10

1

0.1

10

9

8

7

6

5

4

3

2

1

0

HBV

-DN

A(L

og c

opie

s/m

L)

HBsA

g(m

IU/m

l)

Days

2.1 log copies/mL

5.0 mIU/mL

30 mIU/mL

Entecavir

tacrolimus

HISCL HBsAg

HBsAg-HQ

HBVDNA

One more month later detection of conventional HBsAg assay

One month later detection of high-sensitive HBsAg-HQ

HBV DNA was firstly detectable.

(Oone, Tanaka et al., Kanzo. 2019)

Of 13 HBV-reactivated pts,10 (77%) were detected by HBsAg-HQ

-200 0 200 400 600

Days from when HBV DNA became detectable

HBsAg-HQ(-) HISCL(-)

HBsAg-HQ(+) HISCL(-)

HBsAg-HQ(+) HISCL(+)

No. age sex DiagnosisPeak DNA

(IU/mL)

1 81 M multiple myeloma < 20.0

2 54 M malignant lymphoma 28.6

3 81 Mmyelodysplastic syndrome

35.2

4 64 F multiple myeloma 44.8

5 82 Mprimary macroglobulinemia

22.9

6 81 Midiopathic thrombocytopenic purpura

< 20.0

7 61 M multiple myeloma 37.1

8 83 F multiple myeloma 29.5

9 70 Mmetastatic bone sarcoma

< 20.0

10 58 F adult T-cell leukemia 29.5

11 58 M malignant lymphoma 32.4

12 65 F adult T-cell leukemia 21.9

13 76 M rheumatoid arthritis 41.0

HBV reactivation diagnosed by HBsAg-HQIn our hospital

DNA detectable

HBsAg-HQ could be detected in 3 patients, earlier than HBV-DNA.

small S

Open squareHigh-sensitive HBsAgmonitoring might be useful for diagnosing HBV reactivation.

transition

cccDNA

trans

nucleus

IntegrantS

Small S

HBV-resolved patients

(Occult HBV infection)(Oone, Tanaka et al., Kanzo 2019)

Cheap(8 USD)

High sensitive

Advantage of HBsAg-HQ

⇒ Available screening and monitoring tests to detect occult HBV infection and HBV reactivation.

Rapid automatic

(25 min)

Contents







１．Enhancement of cancer-specific immune response

２．Adoptive transfer of CTLs： Cancer-specific TCR

Chimeric antigen receptor (CAR)

３．Inhibition of immune checkpoint：CTLA-4/B7

anti-PD-1/PD-L1

４．Local depletion of Tregs: Anti-CCR4 antibody

（Mogamulizumab）

Current Status of Cancer Immunotherapy

Melanoma,

Non-small cell LK,

Renal cancer,

Gastric cancer

Immune cellsCancer cells

Anti-PD-1

Normal case

Restored T Cells by Blockade of PD-1

Signal Can Kill Cancer Cells

HBV

OPDIVO® (nivolumab): Human IgG4 monoclonal antibody against human PD-1

Melanoma,

non-small cell LK,

renal cancer,

gastric cancer

Immune cellsCancer cells

Anti-PD-1

Normal case

Restored T Cells Kill Cancer CellsRestored T Cells can also attack HBV-Infected Cells?

Blockade of the PD-1 Signal Induces Active Hepatitis B?

(irAE : HBV-related ALT elevation)

Restored T Cells by Blockade of

PD-1 Signal can Kill Cancer Cells

cccDNA

rcDNA

HBV-POL

pgRNA

HBcAg

Nucleocapsid

(HBV DNA)

Anti-HBV effect by blockade of PD-1 signal

mRNAs

IFN-α,λ,γ

receptors

RIG-IIPS

• Molecular mechanisms underlying the induction of HBV-associated innate immune response. (Sato S et al., Immunity 2015)

T cell

Anti-PD-L1 antibody

(MPDL3280A: Phase 2)

Anti-PD-1 antibody

(Nivolumab)

GAPDH

Control PD-1 Block

HBVmRNA

3.5Kb

2.1Kb

HBV-Tg mice

PD-L1

PD-1

• Recovery from HBV-related immune tolerance by blockade of the PD-1 signal, resulting in HBV-RNA reduction along with ALT elevation. (Isogawa et al. PLoS Pathogen 2013)

PD-1 inhibition

Anti-PD-L1 antibody

0

200

400

600

800

1000ALT

U/L

Donor d7

✓ The levels of HBsAg and HBV-DNA should be examined before anti-PD-1 therapy.

✓ If positive, antiviral prophylaxis (NUC) is required.

Research on development of efficient culture cell evaluation system which reproduces the persistent

HBV infection: 2012-2016

Drug screening for developing HBV therapeutics and optimization of the hit compounds

: 2017-2021

Program on the Innovative Development and the Application of New Drugs for Hepatitis B

Yasuhito Tanaka

Emerging Drugs Against HBV

Direct-acting antiviral agents (DAAs)

Host-targeting antiviral agents (HTAs)

Direct-acting antiviral agents (DAAs)

NTCP（Receptor）Attachment

cccDNA

mRNAPolymerase

HBc HBs

Nucleocapsid Reverse transcriptionInhibitor (NUC)

Pregenomic RNA

HBsAg secretioninhibitors

HBV entry inhibitors

RecyclecccDNA inhibitors

Transcription

Endocytosis

HBV Infectious virionHBsAg

Direct-acting antiviral agents (DAAs)① HBV entry inhibitors② Reverse transcription inhibitors③ Capsid assembly modulators④ cccDNA inhibitors⑤ siRNAs, antisense oligos⑥ HBsAg secretion inhibitors

T cell

B cell

Adaptive

DC

Hepatocyte

Innate

Host-targeting agents (HTAs)① Immunomodulators② Therapeutic vaccines

Hepatocyte

Nucleus

siRNAsAntisense

oligos

Immunological assessment of HBeAg-negative chronic hepatitis B patientsresponses following anti-PD-1 treatment

Daniel Verdon et al; AASLD 2017, Washington DCGane E, et al. J Hepatol 2019

Anti-PD-1 blockade with nivolumab

with and without therapeutic

vaccination for virally suppressed

chronic hepatitis B: A pilot study

(Phase Ib study)

Baseline Week 4 Week 12 Week 16

Primary endpoint(12 weeks post Nivolumab)

Sentinel A (n=2)0.1mg/kg Nivolumab

Cohort A (n=12)0.3mg/kg Nivolumab

Cohort B (n=10)0.3mg/kg Nivolumab

40 YU GS-4774

Primary efficacy endpoint: Change in HBsAg log10 IU/mL levels 12 weeks following Nivolumab treatment.

GS-4774 is a heat-inactivated, yeast-based, T-cell vaccine designed to elicit hepatitis B virus (HBV)-specific T-cell responses. YU; yeast units.

One infection of 0.3 mg/kg anti-PD-1, one tenth approved for Melanoma, administered in CHB.

(Gane E, et al. J Hepatol 2019)

One injectionof Nivolumab

Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed patients with HBeAg-negative chronic Hep B (n=24)

-1

-0.75

-0.5

-0.25

0

0.25

-2

-3

-4

-5

Week 12

HB

sAg

chan

ge f

rom

bas

elin

e(L

og

10

IU/m

l)Results: HBsAg change from baseline

-1

-0.75

-0.5

-0.25

0

0.25

-2

-3

-4

-5

Week 24

Sentinel A(0.1mg/kg) Cohort A(0.3mg/kg) Cohort B(0.3mg/kg +GS-4774)

✓ Three patients (14%) showed significant HBsAg declines >0.5

log10 from baseline (p = 0.035), and 1 patient with > 1 log10

reduction in HBsAg at either timepoint.


0

40

80

120

160

200

240

0

250

500

750

1000

1250

1500

Seru

m H

BsA

g (

IU

/m

l) IFNγ

sp

ots

/1

e6

PB

MC

ALT (U

/L)

250

275

Week post-Nivolumab

HBsAg IU/mL

ALT (U/L)

IFNγ CORE Ag

A typical case with HBsAg reductionClinically approved dose 3 mg/kg

for Melanoma etc,

but 0.3 mg/kg for HBV


One patient, whose HBsAg became undetectable at week 20, experienced

a transient ALT flare (grade 3) at week 4 and was accompanied by a

significant increase in peripheral HBsAg-specific T cells at week 24.

Conclusion (Take Home Messages)

✓ All patients should be screened prior to

systemic chemotherapy, by measuring serum

HBV markers including HBsAg, anti-HBc and

anti-HBs, to identify groups at risk of HBV

reactivation.

✓ To prevent hepatitis due to HBV reactivation,

antiviral prophylaxis is recommended for

patients with HBsAg-positive and/or

detectable HBV-DNA at baseline, whereas

regular monitoring of HBV DNA-guided

preemptive antiviral therapy is recommended

for patients with resolved HBV infection.

✓ Refer to a hepatologist.

Acknowledgements

➢ Dr. Sigeru Kusumoto, Nagoya City Univ.

➢ Dr. Junko Kuroda, Nagoya City Univ.

➢ Dr. Masashi Mizokami, Natl Ctr Global Health & Medicine

➢ Dr. Ryuzo Ueda, Aichi Medical Univ.

➢ All the investigators participating in the Japanese

observational study of HBV DNA monitoring and preemptive

antiviral Tx for HBV reactivation in pts with B-NHL following

rituximab-containing Cx

➢ Supported by a grant-in-aid from the Research Program on

Hepatitis from Japan Agency for Medical Research and

Development (AMED) and a grant-in-aid from the Ministry of

Education, Culture, Sports, Science, and Technology

(Scientific Research (C) no. 90423855 to S.K.).

Documents

Management of Hepatitis B reactivationregist2.virology-education.com/.../TokyoHEP/09_tanaka.pdfManagement of Hepatitis B reactivation Nagoya City University Graduate School of Medical