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