Management of Hepatitis B...
Transcript of Management of Hepatitis B...
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
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 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.
Risk Classification for HBV Reactivation after
Immunosuppressive TherapyHBV Infection Status
Immunosuppression
Systemic Cx Allo-SCT
HBsAg(+)
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%
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
Risk Classification for HBV Reactivation after
Immunosuppressive TherapyHBV Infection 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%
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
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
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
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)
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
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)
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. 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
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.
(Gane E, et al. J Hepatol 2019)
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
(Gane E, et al. J Hepatol 2019)
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.).