Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for...

40
Director of Academic Gastroenterology Department, Laiko General Hospital, Athens, Greece George Papatheodoridis Professor in Medicine & Gastroenterology Medical School of National & Kapodistrian University of Athens NAs withdrawal: in whom, when and why

Transcript of Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for...

Page 1: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Director of Academic Gastroenterology Department,

Laiko General Hospital,

Athens, Greece

George Papatheodoridis

Professor in Medicine & Gastroenterology

Medical School of National & Kapodistrian University of Athens

NAs withdrawal: in whom, when and why

Page 2: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Why Bother to Stop NA?

• One pill per day

• Well tolerated and safe

• Inhibition of HBV replication

• ETV/TDF practically no resistance (ETV: only in NA naive)

• Histological improvement, decreased though not

eliminated HCC risk, improved survival

• Cheaper generics are becoming increasingly available

• Risk of relapse, hepatitis flare and hepatic decompensation

in case of NA discontinuation

Page 3: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Reasons for stopping NA therapy

• No need to continue taking a drug (no matter how simple,

safe and cheap) if it does not offer any further benefit

• Some (minimal) risk of side effects - limited safety data

beyond 5-8 years

• Persistence and adherence decline with time

• Increasing cumulative cost (even with cheap drugs) if all

patients continue treatment for life

• Patients often ask for it!

Page 4: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

• Recommendations on when NAs can be stopped vary among

clinical guidelines:

Whom and When can we consider stopping NAs?

HBeAg positive

All international guidelines: stop

NAs after HBeAg seroconversion &

undetectable HBV DNA & 6–12

months consolidation1–3

EASL: perhaps continue until HBsAg

loss (i.e. potentially indefinitely)

particularly in severe fibrosis/

cirrhosis due to high risk of relapse1

1. EASL. J Hepatol 2012;57:167–85. 2. Liaw YF et al. Hepatol Int 2012;6:531–61. 3. Terrault NA et al. Hepatology 2016;63:261–83.

HBeAg negative

All international guidelines:

continue NAs until HBsAg

clearance1–3

APASL: consider withdrawal

after 2 years if HBV DNA

undetectable on three

occasions 6 months apart

(mainly based on cost)2

Page 5: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

HBsAg loss in CHB under NA(s)

HBeAg(+) CHB HBeAg(-) CHB

wk 48 wk 96-104 wk 48 wk 96-104

LAM 1% 1.3% 0.3% 0.9%

ADV 0% - 0%

TBV <1% 1.3% <1% 0.5%

ETV 2% 5% 0.3% -

TDF 3% 6% (11%-wk 240) 0% 0%

Chang et al. NEJM 2006,354:1001-10; Lai et al. NEJM 2006,354:1011-20; Liaw et al. GE 2009,136:486-95;

Marcellin et al. NEJM 2003,348:808-17; Hadziyannis et al. NEJM 2003,348:800-7; GE 2006,131:1743-51;

Lai et al. NEJM 2007,357:2576-88; Heathcote et al. AASLD 2007/2008; Marcellin et al. AASLD 2007/2008/2011

(5% -wk 196)

Page 6: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

NAs withdrawal

in HBeAg-positive CHB

Page 7: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

EFFICACY OF THERAPIES OF FINITE DURATION

IN HBeAg(+)CHB: Sustained off-therapy responses

HBeAg loss

ΗΒeΑg seroconversion to anti-HBe

Pts, %

5-10ΜU d/tiw 180 μg/wk 100 mg/d 10 mg/d 0.5 mg/d 600 mg/d 300 mg/d x4-6 mos x12 mos x12 mos x12 mos x12 mos x12 mos x12 mos

28%

26%

32%

12%21%18%

16%

Wong 1993 Lau 2005 Lai 1998 Marcellin 2003 Chang 2006 Lai 2007 Heathcote 2007

Dienstag 1999

Chang 2006

33% 34%26%

17%24% 24% 26%

22% 22% 21%

Page 8: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

years of therapy

LMV: Chang Antivir Ther 2000, Liaw GE 2000, Leung Hepatology 2001, Lok GE 2003;

ADV: Marcellin NEJM 2003, Marcellin EASL 2005; ETV: Gish AASLD 2005, Chang AASLD 2006;

TBV: Liaw Gastroenterology 2009; TDF: Heathcote AASLD 2010

Anti-HBe seroconversion rates are increasing over time in

HBeAg(+) CHB patients under long-term NA therapy

Patients

with

anti-HBe

sero-

conversion,

%16

17

2328

Page 9: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Post-therapy durability of HBeAg seroconversion

29/

31

30/

39

30/

36

271/

283

Median f-up 103 83 82 36 60 20 37 24 59

(mos)

Leung

2001

Dienstag

2003

Lau

1997

Hsu

2002

LAM Asian Caucas. Asian Mixed

IFNa

Caucasian Taiwan

Spontaneous

Taiwan

69/

71

Lin

2007

Buster

2008

Peg-IFNa

Caucas. Chinese

52/

64

Pati

en

ts w

ith

HB

eA

g

sero

co

nvers

ion

, %

22/

27

42/

95

Wong

2010

Yoon

2005

Reijnders

2010

13/

42

Page 10: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Variability in the rates of off-NAs remission after

anti-HBe seroconversion induced by NAs

• Anti-HBe seroconversion not always

accompanied by HBV DNA undetectability

at NA(s) discontinuation

• Variable durations of consolidation therapy

after anti-HBe seroconversion

• Variable definitions of post-NA(s) response

Page 11: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

DISCONTINUATION OF ORAL ANTIVIRALS IN CHB: A SYSTEMATIC REVIEW

G Papatheodoridis, I Vlachogiannakos, E Cholongitas, K Wursthorn,

C Thomadakis, G Touloumi, J Petersen.

Hepatology 2016; accepted manuscript

Finally included articles: 25

Main inclusion criteria

• CHB adult patients (incl. comp. cirrhosis) who discontinued

NA(s) in virological remission (HBeAg-, undetect. HBV DNA)

• Duration of NA(s) >12 mos and of post-NA(s) f-up ≥12 mos

• Post-NA(s) virological remission: HBV DNA <20,000 IU/mL

Page 12: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

DISCONTINUATION OF ORAL ANTIVIRALS IN CHB: A SYSTEMATIC REVIEW

G Papatheodoridis, I Vlachogiannakos, E Cholongitas, K Wursthorn,

C Thomadakis, G Touloumi, J Petersen.

Hepatology 2016; accepted manuscript

• 14 studies with HBeAg+ patients (n=733)

• 17 studies with HBeAg- patients (n=967)

• Patients with compensated cirrhosis: 18%

• Studies with East Asian: 22, Caucasian: 2, mixed pts: 1

• Primary outcomes: probabilities of virological remission

at 6, 12, 24 and 36 months after NAs discontinuation

(6 studies HBeAg+/-)

Page 13: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

GV Papatheodoridis et al. Hepatology 2016

Forest plots of logit transformed probabilities of virological remission

at 12 months after discontinuation of NA(s) in HBeAg+ patients

Heterogeneity

P<0.001

Page 14: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Patients

with

HBV DNA

<20,000

IU/mL,

%

At 6 12 24 36

months after NA(s) discontinuation

GV Papatheodoridis et al. Hepatology 2016

Rates of virological remission after NAs discontinuation

14 studies, 733 initially HBeAg+ patients

Pooled HBsAg loss: 1%; Durable biochemical remission: 76%

Page 15: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Patients

with

durable

HBeAg

serocon-

version,

%

At 6 12 24

months after NA(s) discontinuation

GV Papatheodoridis et al. Hepatology 2016

Rates of durable HBeAg seroconversion after NAs discontinuation

Systematic review: 6 studies, 289 initially HBeAg+ patients

Page 16: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Patients

with

VR

at 12 mos

after NAs

discontin.,

%

GV Papatheodoridis et al. Hepatology 2016

Rates of virological remission at 12 mos after NAs discontinuation

in initially HBeAg-pos. CHB patients in relation to several factors

VR: virological remission

HBV DNA (IU/mL) <200 <2,000 <20,000 <12 12-24 >24 mos <12 ≥12 mos

VR definition Duration of on-NAs VR Duration of consolidation

therapy after anti-HBe seroc.

P=0.289 P=0.544 P=0.928

Page 17: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

NAs withdrawal in HBeAg-positive CHB

Conclusions

NAs can be safely discontinued in non-cirrhotic

HBeAg-positive CHB patients who achieve anti-HBe

seroconversion and undetectable HBV DNA and

complete 6-12 months of consolidation therapy

• Durable anti-HBe seroconversion: 90% at 1 year &

>85% at 2 years after NAs discontinuation

• HBV DNA <20,000 IU/mL: >60% at 1 year &

>50% at 2-3 years after NAs discontinuation

Page 18: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

NAs withdrawal

in HBeAg-negative CHB

Page 19: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Long-term NA therapy in HBeAg-negative CHB

NA discontinuation in non-cirrhotic HBeAg(-) CHB

patients in virological remission under 4-5 years

ADV therapy

• ~70% of ADV treated pts in virological remission -

discontinued treatment

• ~50% without retreatment after >5 yrs off therapy

• Permanent NA discontinuation: ~35% of all pts

Hadziyannis SJ et al. Gastroenterology 2012;143:629-636

Page 20: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

HBsAg

loss,

%

HBsAg loss in non-cirrhotic patients with HBeAg(-) CHB who

remained in virological remission under ADV for 4-5 years

Hadziyannis SJ et al. Gastroenterology 2012;143:629-636

HBsAg levels at EOT: independent predictor

of HBsAg loss

Page 21: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

• >30 studies in the literature

• Heterogeneous patient populations

• Heterogeneous criteria for NA discontinuation

• Heterogeneous duration of therapy/remission

• Heterogeneous off-therapy response definitions

• Heterogeneous criteria for re-treatment

Discontinuation of NA therapy in

HBeAg-negative CHB

Page 22: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

FINITE CHB: Study Design

TDF-Continue

TDF-Stop

Primary endpoint:

HBsAg loss by Week 144

Wk 0 Wk 48 Wk 144

1:1

Ra

nd

om

iza

tio

n

CHB patients

• HBeAg-negative

• ≥4 years TDF therapy

• Open-label, multicenter, randomised controlled trial

• HBeAg-negative at TDF initiation and discontinuation

• HBV DNA <400 cp/ml for ≥3.5 years before randomisation

• No cirrhosis (Fibroscan ≤10 kPa)

• No history of decompensated cirrhosis

Berg T et al. EASL 2015

Page 23: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

FINITE CHB: Disposition at week 48

Randomized

N=45

Withdrew consent

n=3

Week 48

TDF-Restart

n=3

Week 48

TDF-Stop

n=18

Week 48

TDF-Continue

n=21

TDF-Stop

n=21

TDF-Continue

n=21

Berg T et al. EASL 2015

Page 24: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

FINITE CHB: HBV DNA profiles

HBV DNA became detectable in 21/21 (100%)

of TDF-Stop subjects

HBV DNA up to W48:

– Median: 5.32 log10 IU/mL

– Min: 4.41 log10 IU/mL

– Max: 8.50 log10 IU/mL

At W48*

– 89% (16/18) HBV DNA < 20,000 IU/mL

– 78% (14/18) HBV DNA < 2,000 IU/mL

TDF-Stop (n=21)

Time TDF was restarted

Patients requiring TDF re-initiation (n=3)

HB

V D

NA

(lo

g10

IU/m

L)

Weeks from baseline* TDF-Restart excluded

0 20 40

Berg T et al. EASL 2015

10

9

8

7

6

5

4

3

2

1

0

Page 25: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

FINITE CHB: ALT profiles

Time TDF was restarted

Patients requiring TDF re-initiation (n=3)

TDF-Stop (n=21)

ALT

(U

/L)

559 U/L

983 U/L

Weeks from baseline

ALT peaked at >2xULN in 12/21 TDF-

Stop subjects (57%)

ALT up to W48

– Median: 162 U/L

– Min: 25 U/L

– Max: 983 U/L

At W48*

– 100% (18/18) ALT < 2xULN

– 83% (15/18) ALT < ULN

* TDF-Restart excluded

0 20 40

1000

500

400

300

200

100

0

Berg T et al. EASL 2015

Page 26: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

FINITE CHB: HBsAg ProfilesH

BsA

g (

log

10

IU/m

L)

Time TDF was restarted

Patients requiring TDF re-initiation

Weeks from baseline Weeks from baseline

TDF-Stop (n=21) TDF-Continue (n=21)

HBsAg loss

0 20 40 0 20 40

Berg T et al. EASL 2015

6

5

4

3

2

1

0

Page 27: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

ETV/TDF discontinuation: Greek experience

Virologic relapse (HBV DNA >2000 IU/ml) 40 (93%)

Biochemical relapse (ALT >ULN) 29 (67%)

Acute hepatitis (ALT >10xULN) 10 (23%)

Retreatment 18 (42%)

Post-NAs follow-up, months –median (range) 31 (12-48)

Time of retreatment, months –median (range) 6.5 (1-33)

• 43 non-cirrhotic patients with HBeAg(-) CHB under ETV/TDF

with undetectable HBV DNA for ≥4 years

• Combined criteria for retreatment

Manolakopoulos S et al. AASLD 2015; P2019.

Page 28: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

• 22 studies, 1732 patients

• Virological relapse (HBV DNA >2,000 IU/mL): <70%

• Clinical relapse (HBV DNA >2,000 IU/mL & ALT>ULN): <50%

• Retreatment: <40%

• Relapse associated with shorter treatment, shorter consolidation

therapy and therapy with less potent NAs

• Off NAs severe flares: rare, decompensation: one cirrhotic patient

Discontinuation of NAs in HBeAg-neg. CHB

Systematic review

Chang ML, Liaw YF, Hadziyannis SJ. Aliment Pharmacol Ther 2015;42:243-57.

Page 29: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Forest plots of logit transformed probabilities of virological remission

at 12 months after discontinuation of NA(s) in HBeAg- patients

GV Papatheodoridis et al. Hepatology 2016

Heterogeneity

P<0.001

Page 30: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Patients

with

HBV DNA

<20,000

IU/mL,

%

At 6 12 24 36

months after NA(s) discontinuation

GV Papatheodoridis et al. Hepatology 2016

Rates of virological remission after NAs discontinuation

17 studies, 967 HBeAg- patients

Pooled HBsAg loss: 1.7%; Durable biochemical remission: 57%

Page 31: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Patients

with

VR

at 12 mos

after NAs

discontin.,

%

Rates of virological remission at 12 mos after NAs discontinuation

in HBeAg-neg. CHB patients in relation to several factors

VR: virological remission

HBV DNA (IU/mL) <200 <2,000 <20,000 <12 12-24 >24 mos

VR definition Duration of on-NAs VR

P=0.513 P=0.017

GV Papatheodoridis et al. Hepatology 2016

Page 32: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

• Lower baseline ALT: one study

• Low baseline HBV DNA (<200,000 IU/ml): one study

• Absence of baseline cirrhosis: one study

• Younger age: three studies

• Female gender: one study

• HBV genotype: 0/10 studies

• Type of NA: one study (ETV>LAM/TBV),

0/5 studies (ETV/TDF vs LAM/ADV/TBV)

Factors associated with virological remission

after NAs discontinuation in HBeAg-neg. CHB

GV Papatheodoridis et al. Hepatology 2016

Page 33: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

HBsAg levels as a marker for safe discontinuation

of NA therapy in CHB

• Lower HBsAg levels at end of NAs: Positive association

with off-NAs VR - 298 patients (HBeAg+:124, HBeAg-:158)

Kuo et al, Scand J Gastroenterol 2010;45:75-81; Chan et al, Antivir Ther 2011;16:1249-1257; Kwon

et al, J Med Virol 2013;85:34-42; Chen et al, J Hepatol 2014;61:515-522

• HBsAg levels at end of NAs: No association with

off-NAs VR - 402 patients (HBeAg+:83, HBeAg-:319)

Hadziyannis et al, Gastroenterology 2012;143:629-636; Jeng et al, Hepatology 2013;58:1888-1896;

Seto et al, Gut 2015;64:667-72; Chen et al, J Hepatol 2014;61:515-522

• Lower HBsAg levels at end of NAs: Positive association

with HBsAg loss - 298 patients (HBeAg-:86)

Chan et al, Antivir Ther 2011;16:1249-1257; Hadziyannis et al, Gastroenterology 2012;143:629-636

VR: virological remission

Page 34: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

• Biochemical relapse: 28/72 (39%) patients

• Jaundice: 6/243 (2.5%) patients

• Decompensation: 2/243 (0.8%) patients

• Death: 1/243 (0.4%) patients

• Re-treatment: effective in 242/243 (99.6%) patients

Clinical events after NAs discontinuation

in patients with compensated cirrhosis at baseline

GV Papatheodoridis et al. Hepatology 2016

Page 35: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Guidelines for avoiding risks resulting from

discontinuation of NA(s)

The Japan Society Hepatology

“after discontinuation of treatment, transient abnormalities in the ALT

or the HBV DNA level may be observed in approximately two-thirds

of patients who would finally achieve the inactive carrier state.

Therefore, even if the ALT or HBV DNA levels show mild elevations,

it is possible to follow up without retreatment.”

Tanaka E & Matsumoto A. Hepatol Res 2014;44:1–8

Page 36: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

NAs withdrawal in HBeAg-negative CHB

Conclusions

NAs can be discontinued in non-cirrhotic HBeAg-

negative CHB patients who achieve undetectable

HBV DNA for ≥3 years and can be followed closely

with HBV DNA determinations

• HBV DNA <2,000-20,000 IU/mL: ~50% at 1 year &

~30% at 2-3 years after NAs discontinuation

• Temporary HBV DNA and ALT flares are common

and should not lead to immediate retreatment

Page 37: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Can NAs Be Discontinued in Cirrhotics?

• Compensated cirrhosis: after HBsAg loss

• Decompensated cirrhosis: never (after HBsAg loss?)

• Role of cirrhosis reversal?

• HCC risk after NAs discontinuation?

Page 38: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Potential combinations of PegIFN+NA

PegIFN (up to 48 wks)

NA (variable duration)

PegIFN (up to 48 wks)

NA (variable duration)

PegIFN (up to 48 wks)

NA (variable duration)

Early combinations

NA (variable duration)

NA (variable duration)

PegIFN (up to 48 wks)

PegIFN (up to 48 wks)

Late combinations

Page 39: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe

Future HBV therapies:

new targets, new drugs, new aims

Adapted from Zoulim F et al.

Antiviral Res 2012;96:256–9 HAP: heteroaryldihydro-pyrimidines; HBx: hepatitis B X protein; pg: pregenomic;

siRNA: small interference RNA; rc: relaxed circular; TAF: tenofovir alafenamide fumarate

Immunomodulation

• Toll-like receptors

agonists: GS-9620

• Anti-PD-1 mAb:

BMS-936559, CYT107

• GI13000

• Therapeutic vaccinesHBx

Endosome

rcDNA

cccDNA

Polymerase

pgRNA

Core

Surface

proteins

Targeting cccDNA:

• HAPs

• Chromatin-modifying enzymes

Inhibition of

nucleocapsid

assembly: Bay 41-

4109, NVR 3-778

Polymerase

inhibitors

• Nucleos(t)ide

analogues: TAF,

amdoxovir,

MIV-210, besifovir

• Non-nucleoside:

LB80380

Inhibition of HBsAg release:

REP 9AC, REP2139-CA

RNA interference,

(siRNA): ARC-520

Inhibition of prenylation

(HDV): lonafarnib

Preclinical

Clinical

Entry inhibitors

(HBV/HDV)

• Lipopeptides:

Myrcludex B

Page 40: Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for stopping NA therapy • No need to continue taking a drug (no matter how simple, safe