Hepatitis B Virus Infection - What’s...
Transcript of Hepatitis B Virus Infection - What’s...
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Hepatitis B Virus Infection - What’s New?
Dr. Mamun Al-Mahtab (Shwapnil)
Associate Professor of Hepatology Bangabandhu Sheikh Mujib Medical University
Dhaka, Bangladesh
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Sample size: 1028 apparently healthy subjects Method of study: Questionnaire Study Place: Savar, Dhaka Prevalence: 5.4% (2.5% of world’s HBV population)
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65.8
39
16.5 13.2 12.4
0
20
40
60
80 InjectionVaccination (Smallpox, Cholera)
I/V InfusionSurgeryDental Procedure
Mahtab et. al HBPD Int. 2008
Conventional Risk Factors
64
35.3
11.125.4 22.8
0
20
40
60
80Treatment from Quack
Shaving / Haircut inBarber ShopBody Piercing
Family H/O Hepatitis
Socio-Cultural Risk Factors
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Characteristics of Incidental HBsAg Pos in Bangladesh
……. in a series of 702 HBsAg, 15.6-22.6% had significant hepatic necro-inflammation and 2.4-3.29% had significant hepatic fibrosis.
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Disease Progression in HBeAg-negative HBV
……. in a series of 141 HBeAg -ve CHB patients, 26% had significant hepatic necro-inflammation and 11.7% had significant hepatic fibrosis.
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18.60%20.80%
16.00%18.00%20.00%22.00%
eAg +ve vs eAg -ve CHB
Moderate to Severe CH(eAg +ve)
Moderate to Severe CH(eAg -ve)
19.60%28.30%
0.00%
50.00%Fibrosis > 2 (eAg +ve)
Fibrosis > 2 (eAg -ve)
……. Rather HBeAg -ve may have more severe liver diseases seen in a series of 155 patients
HBeAg-ve Vs HBeAg +ve HBV Infection
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Clinical Spectrum of Occult Hepatitis B
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……. Young HBV patients of immuno-tolerant age group may have significant liver disease in Bangladesh
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ASC CHB LC/HCC
Genotype A Genotype C Genotype D
100%
50%
Distribution of HBV Genotype in Bangladesh
ASC CHB LC/HCC ASC CHB LC/HCC
45/65
12/24
15/65
98/233
7/24 45/233
4/65 40/233
5/24
C
Mahtab et. al Hepatol Int (Suppl) 2017
D A > >
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High Prevalence of Mutation at 1654 and 1754 in HCC
Mutation about 80%
Mahtab et. al Hepatol Int (Suppl) 2017
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Low Prevalence of Mutation at 1654 and 1754 in ASC
Mutation about 20%
Mahtab et. al Hepatol Int (Suppl) 2017
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Treatment recommendations by APASL, AASLD, EASL & different national Hepatology associations
Antivirals for HBV Management
Lmaivudine for CHB Lai et al. N Engl J Med 1998; 339: 61 Lamivudine in USA Dienstag et al. N Engl J Med 1999; 341:1256 Adefovir better than lamivudine Marcellin et al. N Engl J Med 2003; 348: 808 Entavacir better than Adefovir Chang et al. N Engl J Med 2006; 354: 1001 Tenofovir better than adefovir Mercellin et al. N Engl J Med 2008; 359: 2442 Telbuvidine better than lamivudine Lai et al. N Engl J Med 2007; 357: 2576
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In a series of 50 CHB patients, there was no improvement of QoL at 6 months on LAM
Impact of Anti-Viral on QoL
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Final outcome improved: 0 of 25 RCTs All intermediate outcomes improved: 0 of 60 RCTs Some intermediate outcomes improved: in few RCTs
Shamliyan et al. Ann Intern Med 2009
NIH Consensus Conference (Analysis of all RCTs in CHB from 1980-2008)
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Lamivudine plus HBV-Vaccine in Adult CHB
Lamivudine plus Interferon in Paediatric CHB
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Cost of investigations in 1 million Bangladeshi HBV infected USD 1 billion Cost of hospital attendance, surveillance USD 1 billion
Minimum cost of treatment for 50% Bangladeshi HBV infected for 6 yrs. USD 3 billion
Cost of investigation and follow up for HBV CLD USD 3000-10000
Cost of investigation and follow up for HBV HCC USD 10000-50000
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Immunomodulation • Toll-like receptors
agonists, e.g. GS-9620
• Anti-PD-1 mAb, e.g. BMS-936559
• CYT107 • GI13000
• NASVAC
Development stage: preclinical, clinical Zoulim F et al. Antiviral Res 2012 HBV Drug Watch, available at: http://www.hepb.org/professionals/hbf_drug_watch.htm
HBx
Endosome
rcDNA
cccDNA
Polymerase
pgRNA
Core
Surface proteins
Entry inhibitors (HBV/HDV) • Lipopeptides, e.g.
Myrcludex-B
Targeting cccDNA • HAPs • Chromatin-modifying
enzymes
Inhibition of Nucleocapsid Assembly, e.g. Bay 41-4109, NVR1221
Polymerase inhibitors • Nucleoside analogues,
e.g. • TAF, amdoxovir,
MIV-210 • Non-nucleoside, e.g.
LB80380
Inhibition of HBsAg release,
e.g. REP 9AC
RNA interference, (siRNA) e.g. ARC-520
Inhibition of Prenylation (HDV) • Lonafarnib
Future HBV Therapies: New Targets, New Drugs
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HBsAg HBcAg HBsAg + HBcAg
P. pastoris-derived recombinant HBsAg
E. coli-derived HBcAg
Center for Genetic Engineering & Biotechnology, Cuba
Aggregates of 20-30 nm
NASVAC - New Therapeutic Option for HBV
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Optimizing HBsAg/HBcAg Based Intervention in HBV Transgenic Mice
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Phase I Clinical Trial in Healthy Humans
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Phase I/II Clinical Trial in Bangladesh
Safety: Satisfactory Efficacy: HBV DNA negativity and ALT normalized and maintained in 50% Mechanism: HBsAg & HBcAg-specific immune induction and antigen-specific activation of DC
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Number : 151 Diagnosis : CHB Age : 18-52 years HBeAg (+) : 20% HBeAg (-) : 80% ALT : > ULN (HBeAg-negative) > 1.5 x ULN (HBeAg-positive) HBV DNA : > 1 x 103 copies/ml (HBeAg-negative)
> 1 x 104 copies/ml (HBeAg-positive)
Randomly selected in two groups
Patients receiving NASVAC: 75 Patients receiving Peg IFN α: 76
Mahtab et al. Hepatology (Suppl) 2013
Phase III Clinical Trial with NASVAC in CHB
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0
Only nasal 100 microgram (HBsAg/HBcAg)
20
Both nasal (100 microgram) Subcutaneous (100 microgram)
24 weeks EOT
Wk 24 48
48 weeks EOT
NASVAC (every two weeks; 10 times)
Pegylated IFN (weekly; 48 times)
48 Wk 24 48
Study Design: Phase III Clinical Trial
48 weeks EOT EOT 24 weeks EOT
EOT
Mahtab et al. Hepatology (Suppl) 2013
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End of treatment
[EOT]
24 week after EOT
48 week after EOT
Pegylated IFN
NASVAC
Before EOT 24 wk EOT 48 wk EOT Peg-IFN 5 log 2 log 3.5 log 4.7 log NASVAC 5 log 2 log 2.1 log 2.7 log
Before EOT 24 wk EOT 48 wk EOT Peg-IFN Elevated 80% ULN 67% ULN 53% ULN NASVAC Elevated 91% ULN 81% ULN 77% ULN
HBeAg Sero-conversion Before 48 wk EOT Peg-IFN 0% 12.3% NASVAC 0% 33.3%
ALT
HBV DNA
NASVAC versus Peg-IFN 1 Year After EOT (All treatment free after EOT)
Fibrosis (48 wk after EOT) >11.0 kPa >18.0 kPA Peg-IFN 19.7% 9.2% NASVAC 8.2% 0%
HBV DNA
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Kinetics of qHBsAg after NASVAC & Peg-IFN α
Peg-IFN NASVAC
Mahtab et al. Hepatology (Suppl) 2014
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Registered as Licensed Drug in Cuba
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Current Status
Multi-centre clinical trial for registration ongoing in Russia Multi-centre clinical trial for registration to kick off in China Ethical approval for clinical trial obtained in Japan
Multi-centre clinical trial ongoing involving 7 Asian countries i.e. South Korea, Taiwan, Thailand, Hong Kong, Indonesia, New Zealand & Australia
Expected to be commercialized in 2019-2020
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N O
O
N O
O
O
S - O P
N O
O
O
S - O P
N O
O
S - O P
N
N N
N H 2
N
N N
N H 2
N
N H 2
O
N
N H 2
O
O
O
S - O P
Activity independent of immuno-stimulatory mechanisms Lateral interaction with amphipathic domains dependent on length of polymer Phosphorilation essential for activity
Nucleic Acid Polymer (NAP) - HBsAg Release Inhibitor
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Infected hepatocyte
Virions
HBeAg
Subviral particles (bulk of serum HBsAg)
Capsids
cccDNA
HBsAg • Sequesters anti-HBs • Suppresses innate immunity • Suppresses T-cell proliferation • Suppresses cytokine signaling • Suppresses immunotherapy
HBsAg removal will be required to achieve high
SVR rates
Immunological Disorder in CHB caused by HBsAg
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Infected hepatocyte
Virions
HBeAg Capsids
cccDNA
HBsAg-mediated Immune-suppression
removed
Restoration of host immune response!!
NAPs Block Release of Sub-viral Particles
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0 10 20 30 40 50 60
0
1000
2000
40000
80000
120000
160000
seru
m H
BsAg
(IU
/ m
l)
Weeks of treatment
Patient 1 (dose escalation) Patient 2 (dose escalation) Patient 2 (2nd course) Patient 3 Patient 4 Patient 5 Patient 6 Patient 7
REP 9AC ‘Mono-Therapy’ in Treatment Naive CHB
7/7 patients with HBsAg clearance
N = 7
0 10 20 30 40 50 600
20
40
60
80
500
1000
1500
2000
anti-
HB
s (m
IU /
ml)
Weeks of treatment
Patient 1 (dose escalation) Patient 2 (dose escalation) Patient 2 (2nd course) Patient 3 Patient 4 Patient 5 Patient 6 Patient 7
HBsAg Anti-HBs
Anti-HBs response is heterogenous, but seen in all 7
Mahtab et al. PLOS One 2016
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0 10 20 30 40 50 60
1E+01
1E+02
1E+03
1E+04
1E+05
1E+06
1E+07
1E+08
1E+09
1E+10
1E+11
1E+12
HBV
DN
A (c
opie
s /m
l)
Weeks of treatment
Patient 1 (dose escalation) Patient 3 Patient 5 Patient 6
Restoration of immunological control in 4/7
REP 9AC ‘Mono-Therapy’ in Treatment Naive CHB
0 50 100 150 200 250 300
1E+01
1E+02
1E+03
1E+04
1E+05
1E+06
1E+07
1E+08
1E+09
1E+10
1E+11
1E+12
HB
V D
NA
(cop
ies
/ml)
Weeks after start of treatment
Patient 1 (treatment) Patient 1 (follow up) Patient 5 (treatment) Patient 5 (followup)
Long-term off treatment SVR in 2/7
N = 7 Mahtab et al. PLOS One 2016
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0 10 20 30 40 50 600
5000
10000
15000
40000
60000
80000
100000
120000
140000
seru
m H
BsAg
(IU
/ m
l)
Weeks of treatment
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9
HBsAg clearance in 9/12
‘Addition’ of Peg IFN or Thymosin α to REP 9AC Mono-Therapy after HBsAg Clearance in Naive CHB
N = 12
0 10 20 30 40 50 600
100
200
600
800
1000
1200
1400
seru
m a
nti-H
Bs (m
IU /
ml)
Weeks of treatment
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9
Restoration of immunological control in 9/12
HBsAg Anti-HBs
Mahtab et al. PLOS One 2016
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0 10 20 30 40 50 60 701E+01
1E+02
1E+03
1E+04
1E+05
1E+06
1E+07
1E+08
1E+09
1E+10
seru
m H
BV D
NA (c
opies
/ m
l)
Weeks of treatment
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9
LLOQ
ETR in 9/12
HBV DNA
‘Addition’ of Peg IFN or Thymosin α to REP 9AC Mono-Therapy after HBsAg Clearance in Naive CHB
0 10 20 30 40 50 60 70 80 90 1001E+01
1E+02
1E+03
1E+04
1E+05
1E+06
1E+07
1E+08
1E+09
1E+10
seru
m H
BV D
NA
(cop
ies
/ ml)
Weeks of follow up
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9
Long-term off treatment SVR in 4/12
N = 12 Mahtab et al. PLOS One 2016
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0 10 20 30 40 500
1000
2000
3000
4000
100001200014000160001800020000
seru
m H
BsAg
(IU
/ ml)
Weeks of treatment
Patient 1 (17 wks @ 500 mg) Patient 2 (17 wks @ 500 mg) Patient 3 (17 wks @ 500 mg) Patient 4 (10 wks @ 100 -> 30 wks @ 200 mg) Patient 5 (10 wks @ 100 -> 30 wks @ 200 mg)
+ ETV
‘Upfront Combination Therapy’ with Peg IFN or Thymosin α Plus REP 9AC in CHB
HBsAg clearance in 5/5
N = 5
Restoration of immunological control in 5/5
HBsAg Anti-HBs
0 10 20 30 40 50
0
500
1000
1500
seru
m a
nti-H
Bs
(m
IU /
ml)
Weeks of treatment
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
+ ETV
Mahtab et al. PLOS One 2016
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0 10 20 30 40 501E+01
1E+02
1E+03
1E+04
1E+05
1E+06
1E+07
1E+08
1E+09
seru
m H
BV D
NA (
copi
es /
ml)
Weeks of treatment
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
+ ETV
Mahtab et al. PLOS One 2016
‘Upfront Combination Therapy’ with Peg IFN or Thymosin α Plus REP 9AC in CHB
ETR in 5/5
HBV DNA
Long-term off treatment SVR in 3/5
0 10 20 30 40 50 601E+01
1E+02
1E+03
1E+04
1E+05
1E+06
1E+07
1E+08
1E+09
seru
m H
BV
DN
A (
copi
es /
ml)
Weeks of follow up
Patient 2 Patient 3 Patient 4 Patient 5
+ ETV
N = 5
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Present Status
Phase II clinical trial with REP 9AC in combination with Peg IFN α 2a currently ongoing in Europe 12 patients with HBV/HDV co-infection included
Simultaneously reduces HBsAg and HDV RNA
REP 2139 Expert Committee Meeting, Vienna, April 2015
![Page 40: Hepatitis B Virus Infection - What’s New?bsmedicine.org/congress/2016_2/Dr._Mamun_Al_Mahtab.pdfMahtab et. al Hepatol Int (Suppl) 2017. Low Prevalence of Mutation at 1654 and 1754](https://reader035.fdocuments.net/reader035/viewer/2022081617/60229866d21ecc3a993ef165/html5/thumbnails/40.jpg)
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Recognition from the Hon’ble PM
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Kobi Guru’s observation about Bengalis
Bangabandhu’s historical saying on return home on January 10, 1972