Hepatitis B Virus Infection - What’s New?
Dr. Mamun Al-Mahtab (Shwapnil)
Associate Professor of Hepatology Bangabandhu Sheikh Mujib Medical University
Dhaka, Bangladesh
Sample size: 1028 apparently healthy subjects Method of study: Questionnaire Study Place: Savar, Dhaka Prevalence: 5.4% (2.5% of world’s HBV population)
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
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.
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.
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
Clinical Spectrum of Occult Hepatitis B
……. Young HBV patients of immuno-tolerant age group may have significant liver disease in Bangladesh
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 > >
High Prevalence of Mutation at 1654 and 1754 in HCC
Mutation about 80%
Mahtab et. al Hepatol Int (Suppl) 2017
Low Prevalence of Mutation at 1654 and 1754 in ASC
Mutation about 20%
Mahtab et. al Hepatol Int (Suppl) 2017
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
In a series of 50 CHB patients, there was no improvement of QoL at 6 months on LAM
Impact of Anti-Viral on QoL
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)
Lamivudine plus HBV-Vaccine in Adult CHB
Lamivudine plus Interferon in Paediatric CHB
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
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
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
Optimizing HBsAg/HBcAg Based Intervention in HBV Transgenic Mice
Phase I Clinical Trial in Healthy Humans
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
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
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
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
Kinetics of qHBsAg after NASVAC & Peg-IFN α
Peg-IFN NASVAC
Mahtab et al. Hepatology (Suppl) 2014
Registered as Licensed Drug in Cuba
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
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
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
Infected hepatocyte
Virions
HBeAg Capsids
cccDNA
HBsAg-mediated Immune-suppression
removed
Restoration of host immune response!!
NAPs Block Release of Sub-viral Particles
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
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
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
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
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
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
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
Recognition from the Hon’ble PM
Kobi Guru’s observation about Bengalis
Bangabandhu’s historical saying on return home on January 10, 1972