Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for...
Transcript of Livemedia.gr - NAs withdrawal: in whom, when and …...in case of NA discontinuation Reasons for...
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
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
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!
• 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
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)
NAs withdrawal
in HBeAg-positive CHB
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%
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
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
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
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
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+/-)
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
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%
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
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
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
NAs withdrawal
in HBeAg-negative CHB
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
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
• >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
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
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
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
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
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
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.
• 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.
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
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%
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
• 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
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
• 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
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
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
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?
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
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