Advances in treatment of HBVAlfredo Marzano

San Giovanni Battista Hospital

University of Turin

Italy

I

Outline

• General background

• Therapy

• Aims

• Strategies

• Efficacy

• Drugs and virus

• Clinical results

• Summary

I

Background

HBVHBsAg+ > 400 millions

antiHBc+ > 2 billions

8 different genotypes.

High replicative activity : 1011-12 virions/daily

High Mutations rate: 1 every 100,000

Acute

InfectionChronic

Infection Cirrhosis Death

1. Torresi, J, Locarnini, S. Gastroenterology. 2000.

2. Fattovich, G, Giustina, G, Schalm, SW, et al. Hepatology. 1995.

3. Moyer, LA, Mast, EE. Am J Prev Med. 1994.

4. Perrillo, R, et al. Hepatology. 2001.

5%-10% of

chronic HBV-

infected

individuals1

Liver

Failure(Decomp.)

30% of chronic

HBV-infected

individuals1

• >90% of infected

children progress

to chronic disease

• <5% of infected

immunocompetent

adults progress to

chronic disease1

23% of patients

decompensate

within 5 years of

developing

cirrhosis 3

Liver

Cancer

(HCC)

Chronic HBV is the

6th leading cause of

liver transplantation

in the US 4

Liver

Transplantation

Inactive

carrier

3%/yr

3%/yr

Natural History of CHBDisease

Natural history of CHBVirological aspects (infection)

Adapted by Kim HJ & Lok ASF. Hepatology 2006

Anti-HBe

HBeAg

HBV DNA

ALT

ReactivationInactive

carrier state

Immune

clearance

Immune

tolerant

HBsAg+ (overt) HBsAg- (OBI)

e+CHB

e-CHB

HBV DNA

IC ACIC

qHBsAg H

Bs

Ag

(lo

g IU

/mL

)

Immune tolerance (7)

e+ active CHB (25)

e seroconversion (17)

e- active CHB (46)

e- inactive CHB (22)

Chan HL et al. Hepatology 2010

117 chronic hepatitis B patients

followed for 9916 months; number of visits 17 (8–49)

Cirrhosis

Gaia, J Hepatol 2011

* Oliveri, WJG 2008

Staging

Liver biopsy and Fibroscan

6*Inactive

OBI

Immunotollerant

Chronic Hepatitis

I

Therapyaims

Antiviral Therapy in HBVGoals

HBV DNA

IU

qHBsAg

IU

HBeAg

AC > 2000 > 1000 Pos/neg

IC < 2000 <1000 neg

neg <100 neg

OBI neg neg neg

STOP

Evolution

Cirrhosis (regression)

Portal hypertension

Liver transplantation

HCC

Mortality

I

TherapyStrategies

Therapeutic strategies

Curative (defined time)

Suppressive (NUC) (undefined time)

PEG

NUC (e+)

PEGSuppressive (NUC)

induction

Curative

Suppressive (NUC) PEG

ConsolidationCurative

Immune modulation (theraputic vaccines)

This topic falls outside my time

I

TherapyEfficacy

PEG-IFNPeg-IFN in HBeAg-positive

Marcellin, Gastroenterology 2009

e+

e-

50%

HBsAg

clearance

J Hepatology 2012

Better response in genotype non-D/E

Marengo & Marzano

Antivir Ther 2013

100%

TDF

Marengo & Marzano

APT 2014

ETV

Pangenotypic

I

TherapyDrugs and Virus

Why the mono-therapy is effective?

Virus and Drugs characteristics

Suppression vs. cure:

viral biology is the basis

Kieffer TL, et al. J Antimicrob Chemother. 2010;65:202-212.

HCV6 genotypes

(No Latent Reservoir)

HCV RNA

Definitive Viral

Clearance

Host DNA

Host cell

Nucleus

cccDNA

Long-Term

Reduction of Viral

Replication to

Lowest Possible

Level

HBV 10 genotypes

(Latent Reservoir)

cccDNA = covalently closed circular DNA.

Suppression Cure

Long-time cccDNA

“Low “ replicative space

Drugs

Pharmacologic barrier

Intracellular drugs levels and resistance

I generation (high drug levels)

Low toxicity, medium potency

Time

Intr

acell

ula

r C

on

cen

trati

on

s

Drug level required

to overcome WT

virus

Drug toxicity

thresholdLAM

Drug level required

to overcome

“resistant” virus

Modified from Moyle G, et al. Drugs. 1996

Drug level required

to overcome

“resistant” virus

Time

Intr

acell

ula

r C

on

cen

trati

on

s

ADF

Drug level required

to overcome WT

virus

Drug toxicity

threshold

Drugs

Pharmacologic barrier

Intracellular drugs levels and resistance

II generation (low drug levels)

High toxicity, medium potency

Modified from Moyle G, et al. Drugs. 1996

Drug level required

to overcome

“resistant” virus

Modified from Moyle G, et al. Drugs. 1996

Time

Intr

acell

ula

r C

on

cen

trati

on

s

Drug level required

to overcome WT

virus

Drug toxicity

thresholdTDF, ETV

Drugs

Pharmacologic barrier

Intracellular drugs levels and resistance

III generation (high drug levels)

Low toxicity, high potency

Drug levels, Genetic barrier and the virus

ADV LAM ETV, TDF (?)

HBV

HCV

W

W

WW

W

W

W

W

WW

WW

W

W

W

W

WW

W

W

W

W

WW

WW

W

WM

on

o-th

era

py

III

II

I

M

III

II

I

MM

MM

MM

MM

MM

MM

M

M

HCV

W

W

WW

W

W

W

W

WW

WW

W

W

HCV

W

W

WW

W

W

W

W

WW

WW

W

W

M

Mo

no

-the

rap

y

MM

M

MMM

hours days

HCV RNA+

HBV

W

W

WW

W

W

W

W

WW

WW

W

W

HBV

W

W

WW

W

W

W

W

WW

WW

W

W

M

M

M

Replicative spaceNative

XX

XX

X

months years

HBV DNA- (II-III generation)

29

70

18

67

0

11

49

0.5

38

0.20

24

Genetic Barrier

Incidence of Resistance in NUC-naïve Patients

0

20

40

60

80

LAM ADV LDT ETV TDF

Pati

en

ts (

%)

17

3 1.2?4

01.2

1.20

adapted from EASL HBV Guidelines, J Hepatol 2012

1st generation

2nd generation

3rd generation

*Collation of currently available data – not from head-to-head studies

0 0

I

TherapyClinical Results

Can we reach clinical results

with the NUCs?

Marcellin P; The Lancet 2013

Regression of histological cirrhosis with TDF

N=57N=57

* Median time of long-term biopsy: 6 years (range: 3–7 years)

Reversal of fibrosis/cirrhosis with ETV

Chang TT, Hepatology 2010

Marengo, & Marzano Antiviral Therapy 2013

Decompensation Death

* 2 CH

CH

Cirrhosis

Clinical experience with III gen NUCs:

Entecavir 100 pts (55 compensated cirrhosis)

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96 108 120 Months

27 24 19 9 4 3

80%

2127 15 8 4

27 26 23 2

0

14 92427 21 18 14

12%

EV progression

EV regression

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96 108 120

Patients

at risk80 78 74 62 45 3380 6778 56 39

8%

EV progression

Changes of esophageal varices (EV) in

compensated cirrhotics treated with LAM±TDF for 10 years

No varices at baseline (n=80)

Lampertico et al, submitted 2013

F1 varices at baseline (n=27)

Overall, EV worsening rate per year: 0.9%*

* 6 of 7 progressors (86%) had either LMV-R and/or HCC

Decompensated cirrhosis

Mutimer DJ, Gut 2012

2429 pts

Prophylaxis of hepatitis B recurrence after LTCholangitas, Am J Transpl 2013

Excellent results but……

HCC remains the residual problem

Expected annual risk in Europe ( untreated) 0.2% (CH) -2% (Cirrhosis)

0

1

2

3

4

Liaw

(2004)

1.5%

HC

C p

er

year

(%)

Papatheod.

(2010)

HCC rates in NUC-naïve cirrhotic patients

long-term responding to NUC (LAM-exp)

2.4%2.5%

Papatheod.

(2011)

2.8%

Kurokawa

(2012)

Aghemo A et al, J Hepatol 2012

211 81Num. of pts: 62 42

LAM LAMDrug: LAM LAM

RCT ReviewStudy: Retrosp. Retrosp.

3 yrs 2 yrsFollow-up: 6 yrs 5 yrs

Clinical experience with ETV:

HCC in 472 (gen B-C) vs 1143 untreated patients

Hosaka, Hepatology 2012

1.4% y

0.5% y

HCC rates in ETV or TDF treated CHB pts

European multicenter study

0%

10%

20%

30%

40%

50%

Cu

mu

lative

pro

ba

bili

ty o

f H

CC

0 1 2 3 4 5

Years of NUC therapy

HCC rates/yr in chronic hepatitis: 0.5%

HCC rates/yr in compensated cirrhotics: 4.2%

21%

(N=1231 patients, 54% naive, 55% TDF, 39 months follow-up)

Papatheodoridis G & Lampertico P et al, AASLD 2013

Compensated Cirrhosis

Chronic hepatitis 5%

4% y

1% y

LT for HBV-related cirrhosis in US and Europe

Decompens.vs

HCC

Van Bommel, Liver Int 2013; Burra & Marzano, J Hepatol 2013

HBV …. too

Summary