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Hepatitis B Virus therapy
Maria Buti Hospital Universitario Valle Hebron Barcelona Spain
Disclosures
Advisor: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis
Lecturer: Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis
Clinical trials: Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis, Roche
Immune tolerance Immune active Immune control HBeAg Anti-HBe
HBV DNA log10 IU/ml
ALT (U/L)
HBeAg or anti-HBe
HBsAg log10 IU/ml
5 4 3 2
500
100 20
Natural history of CHB
Janssen, et al. Gut 2012
Treatment indicated
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Liaw Y-F, et al. Hepatol Int 2012;11:163645 ALT: alanine aminotransferase; HBV: hepatitis B virus
Treatment indicated Chronic hepatitis
ALT elevated HBV DNA >2000 IU/mL Fibrosis
Cirrhosis Decompensated cirrhosis
Treatment not indicated Immune tolerant HBV HBV carrier state
Chronic hepatitis B infection
What can be achieved now
In immune tolerant patients
In patients with CHB and cirrhosis
In decompensated patients
CHB: chronic hepatitis B
Long-term follow-up of immune tolerant patients
Consecutive immune tolerant patients HBsAg- and HBeAg- for
> 6 months Normal ALT levels on
3 consecutive readings over 6 months
HBV DNA >107 copies/mL 57 patients followed up
for 5 years 84% of patients remained
immune tolerant at Year 5 No HCC
0
5
10
15
20
25
30
35
F0 F1 F2
BaselinebiopsyBiopsy at5 years
Hui CK, et al. Hepatology 2007;46:395401 HBsAg: hepatitis B surface antigen;
HBeAg: hepatitis B e antigen; HCC: hepatocellular carcinoma
Pat
ient
s (%
)
What can be achieved now in immune tolerant patients?
Chan HL, et al. Gastroenterology 2014;146:12408 FTC/TDF and FTC are investigational agents and not licensed for use in CHB; TDF: tenofovir disoproxil fumarate; FTC: emtricitabine; UNL: upper normal limit
HBV DNA 108 copies/mL ALT ULN
(N=126)
Randomised to TDF for 192 weeks
(n=64)
Completed study through Week 192
(n=54; 87%)
Randomised to FTC/TDF for 192 weeks
(n=62)
Completed study through Week 192
(n=53; 83%)
Discontinued treatment before Week 192
(n=11; 17%)
Discontinued treatment before Week 192
(n=8; 13%)
TDF and FTC/TDF in patients with normal ALT and high HBV DNA Phase 2, randomised, double-blind study in HBeAg-positive patients
HBV DNA suppression in immune tolerant patients
Chan HL, et al. Gastroenterology 2014;146:12408
100
80
60
40
20
0 0 16 32 48 64 80 96 112 128 144 160 176 192
Study week
Pat
ient
s (%
)
FTC/TDF 76%
TDF 55%
6% TDF patients and 2% TDF/FTC achieved HBeAg loss 5% TDF patients and 0% TDF/FTC achieved HBeAg seroconversion There were no cases of HBsAg loss/seroconversion No patients developed HCC or clinical events
What can be achieved now?
In immune tolerant patients
In patients with CHB and cirrhosis
In decompensated patients
Liaw Y-F, et al. Hepatol Int 2012;11:163645
Treatment indicated Chronic hepatitis
ALT elevated HBV DNA >2000 IU/mL Fibrosis
Cirrhosis Decompensated cirrhosis
Treatment not indicated Immune tolerant HBV HBV carrier state
Chronic hepatitis B infection
Approved Agents used to Treat HBV
Lamivudine
Telbivudine
Entecavir
Adefovir
Interferon alpha-2a
Peginterferon alpha-2b
Tenofovir
Chart1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2007
0
0
0
0
Year
Number of FDA-Approved Agents
Sheet1
19921993199419951996199719981999200020012002200320042005200620072008200920102011
Number of FDA-Approved Agents0000000000000000000
Therapeutic strategies for chronic hepatitis B
Short-term "curative" treatment
Years
HBV DNA < 2000 IU/ml ALT < UNL (anti-HBe)
On treatment response
HBsAg Loss
Follow-up (mo/yrs) IFN
Long-term "suppressive" treatment
HBV DNA undetectable by PCR (
Therapeutic Strategies for Chronic Hepatitis B
Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Positive Patients
HBeAg-POSITIVE Patients: Week 72 Treatment Response
Lau GKK, et. al. N Engl J Med. 2005;352:2682-95.
P < 0.001
P < 0.001
P = 0.006
P = 0.002
P = 0.02
P < 0.001
Chart1
0.140.140.05
0.410.390.28
0.320.270.19
Peg-INF alfa-2a
Peg-INF alfa-2a + Lamivudine
Lamivudine
Patients (%)
Sheet1
Peg-INF alfa-2aPeg-INF alfa-2a + LamivudineLamivudine
HBV DNA < 400 copies/ml14%14%5%
ALT Normalization41%39%28%
HBeAg Seroconversion32%27%19%
Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Negative Patients
HBeAg-NEGATIVE Patients: Week 72 Treatment Response
Marcellin P, et. al. N Engl J Med. 2004;351:1206-7.
P=0.007
P=0.003 P=0.849
P=0.004
P=0.003 P=0.915
Chart1
0.430.440.29
0.590.60.44
Peg-INF alfa-2a
Peg-INF alfa-2a + Lamivudine
Lamivudine
Patients (%)
Sheet1
Peg-INF alfa-2aPeg-INF alfa-2a + LamivudineLamivudine
HBV DNA < 20,000 copies/ml43%44%29%
ALT Normalization59%60%44%
Impact of (peg)-IFN therapy on CHB
Safety profile well known
Progression to cirrhosis prevented
Clinical decompensation prevented
HCC reduced (?)
Improved patient survival
Immune control status in 30% of patients
How can we improve PEG-IFN efficacy ?
pretreament predictors of response High ALT levels
Low levels HBV DNA
Genotype A
Young people
on-treatment predictors of response
Response-guided therapy (RGT) using HBsAg levels in Peg-IFN-treated patients:
to identify non responders
Week 12:
- No decline of HBsAg (A,D) - HBsAg >20,000 IU/mL (B,C)
Week 24:
- HBsAg >20,000 IU/ml (A,B,C,D)
Week 12:
- No decline in HBsAg +
Response-guided therapy by HBsAg levels in Peg-IFN-treated patients: to identify non
responders
Week 12:
- No decline of HBsAg (A,D) - HBsAg >20,000 IU/mL (B,C)
Week 24:
- HBsAg >20,000 IU/ml (A,B,C,D)
Week 12:
- No decline in HBsAg +
Therapeutic Strategies for Chronic Hepatitis B
High virological responses with long-term ETV or TDF
Response
ETV TDF
HBeAg+ patients Year 51
HBeAg- patients Year 32,a
HBeAg+ patients Year 83
HBeAg- patients Year 83
HBV DNA suppressionb 94% (88/94) 95%
(54/57) 98%
(159/160) 99%
(271/273)
Resistance 1% (n=1) NR 0% 0%
HBsAg loss (seroconversion) NR NR
12.9% (10.3%)
1.1% (
91 94 100 100
88 95 91
100
0
20
40
60
80
100
Week 48 Week 96 Week 144 Week 192
% P
atie
nts
with
VR
, H
BV
DN
A <
69 IU
/mL
TN TE
CIBERHEP: Efficacy of TDF in Treatment nave and Treatment Experienced patients
74 84 86
100
74 82 85
100
0
20
40
60
80
100
Week 48 Week 96 Week 144 Week 192
% P
atie
nts
with
VR
, H
BV
DN
A <
69 IU
/mL
Tabernero D. EASL 2014; Poster 1058 TE: treatment experienced; TN: treatment nave
Viral suppression was similar between TN and TE patients, with HBeAg loss
occurring more in TN patients
HBsAg loss: n=4 (1 HBsAg seroconversion)
HBeAg-negative HBeAg-positive
23 19
TN, N TE, N
19 17
14 13
3 8
65 48
TN, N TE, N
50 40
26 33
13 25
Patients (N=370) from 48 Spanish centres treated for 12295 weeks
0 48 96 144 192 0
30
60
90
120
150
180
210
MD
RD
(ml/m
in/1
.73m
2 )
Week
VIREAL study: high rates of virological response, regardless of age Subgroup (n=48) of elderly patients (65 years)
Incidence of comorbidities in elderly patients: 35% hypertension 17% diabetes 58% F3F4 (METAVIR) at baseline
Causse X. EASL 2014; Poster 1062
TDF has not been studied in patients >65 years. As elderly patients are more likely to have decreased renal function, caution is required
in these patients (Viread SmPC, March 2014)
Patie
nts
with
HBV
DN
A
Liver fibrosis regression and cirrhosis reversal over 5 years of treatment with TDF
N=348 had biopsies at baseline and Year 5 (96 with cirrhosis)
Marcellin P, et al. Lancet 2013;381:46875 Histologically evaluable patients in the
long-term histology cohort
0
20
40
60
80
100
Baseline Year 1 Year 5
Missing6543210
Pat
ient
s (%
)
P
Characteristics of patients shown to be associated with reversal of cirrhosis with TDF
Marcellin P, et al. Lancet 2013;381:46875 BMI: body mass index; SD: standard deviation
Characteristic No cirrhosis at Year 5 (n=71)
Cirrhosis at Year 5 (n=25)
P value
Mean BMI at baseline, kg/m2 (SD)
25.7 (3.7) 29.0 (4.4) 0.0007
BMI (kg/m2) at baseline, %
Japanese cohorts: significantly reduced HCC incidence with ETV compared with controls
in cirrhotic patients
Hosaka T, et al. Hepatology 2013;58:98107 LAM: lamivudine
Control ETV LAM
HCC
79 49 85
79 49 85
72 41 76
17 29 47
ETV LAM
Control
Treatment duration (years)
Cum
ulat
ive
HC
C ra
te (%
)
0 1 2 3 4 5
0
20
30
40
50
10
No. at risk 53 35 65
35 32 64
Control
LAM
11.4%
20.9%
2.6%
28.5%
4.3%
19.7%
7.0%
6
ETV 7.0%
22.2%
38.9%
4.8%
12.2%
Cirrhotics Log-rank test:
ETV vs LAM: P=0.043 ETV vs control: P
Lower risk of death/transplantation with ETV than with LAM
Death or transplantation HCC
Lim Y-S, et al. Gastroenterology 2014:doi: 10.1053/j.gastro.2014.02.033
1792 1792
1778 1777
1740 1436
1660 966
1601 563
1531 224
LAM ETV
No. at risk
Est
imat
ed c
umul
ativ
e in
cide
nce
of
dea
th o
r tra
nspl
anta
tion
(%)
0 1 3 5 2 4 6
0
40
60
80
100
20
Years after starting treatment
1389 21
P
When to stop NA therapy?
EASL 2012 guidelines
HBeAg positive
A) Confirmed anti-HBe seroconversion (and undetectable HBV DNA) after at least 12 months of consolidation* B) Confirmed HBsAg loss and anti-HBs seroconversion
HBeAg negative Confirmed HBsAg loss and anti-HBs seroconversion
Cirrhotics Confirmed HBsAg loss and anti-HBs seroconversion
Adapted from EASL Clinical Practice Guidelines. J Hepatol 2012;57:16785
*A proportion of patients who discontinue nucleos(t)ide analogue (NA) therapy after anti-HBe seroconversion may require retreatment,
since they fail to sustain their serological and/or virological response; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen
Off-therapy durability of response to ETV in HBeAg-negative CHB from Taiwan
95 patients (39 cirrhotic) treated with ETV for 24 (1359) months
Stopping rule: undetectable HBV DNA on 3 occasions at least 6 months apart
Response after treatment discontinuation compared with LAM or LdT from historical data
Cumulative relapse rates in Year 1: Virological relapse: 58% Clinical relapse: 45%
No good predictors of relapse
Jeng WJ, et al. Hepatology 2013;58:188896
0 90 180 270 360 Time to relapse (days)
0
20
40
60
80
100
Off
ther
apy
cum
ulat
ive
rela
pse
(%)
LAM or LdT
P=0.027
ETV
HBsAg loss
qHBsAg predicts HBsAg loss and HBV relapse after LAM discontinuation in HBeAg -ve
Chen CH, et al. J Hepatol 2014; doi.org/10.1016/j.jhep.2014.04.029 (epub ahead of print)
*Defined as serum HBV DNA >2,000 IU/mL in 2 measurements at least 3 months apart
HBsAg 1201000 IU/mL 60
40
20
0
0 52 104 156 208 260 312 364 C
umul
ativ
e in
cide
nce
of H
BsA
g lo
ss
Duration of follow-up (weeks)
HBsAg
Stopping TDF After Long-Term Virologic Suppression in
HBeAg-Negative CHB
32
FINITE CHB, a randomized study in non cirrhotic HBeAg-ve patients with 4 yrs TDF therapy and undetectable HBV DNA
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
86% of TDF-Stop subjects did not restart TDF by Week 48
Berg, EASL, 2015, O119
33
TDF-Stop: HBsAg loss, HBV DNA, ALT, TDF-Restart
FINITE CHB study 48 weeks outcome after therapy discontinuation
5%
24%
10%
10%
52% 48%
38%
10%
5%
57%
19%
14%
10%
Berg, EASL, 2015, O119
Grfico1
9.52380952389.523809523823.80952380954.761904761952.3809523810
9.5238095238038.0952380952047.6190476194.7619047619
14.2857142857019.0476190476057.14285714299.5238095238
TDF-Restart
HBV DNA >2000, ALT >2 x ULN
HBV DNA >2000, ALT 2000, ALT 2000, ALT
34
* TDF-Restart
-1 1 3 5HBsAg (log10 reduction)
-1 1 3 5HBsAg (log10 reduction)
TDF-Stop (n=21) TDF-Continue (n=20)
*
*
*
HBsAg Log10 Reduction: Median 0.283 Mean 0.773 HBsAg loss n=2
HBsAg Log10 Reduction: Median 0.088 Mean 0.109 HBsAg loss n=0
Week 48 HBsAg log10 Reduction (Individual Patients)
FINITE CHB. HBsAg levels between Patients who
TDF stopped and those who TDF continued
Stopping TDF was associated with a more profound decline in HBsAg levels compared to continuous TDF
HBsAg loss HBsAg loss
Berg, EASL, 2015, O119
HBsAg Clearance After Addition of PegIFN for 48 Weeks in HBeAg-Negative CHB Patients on NUCs
35 Bourliere, EASL, 2015, O112
Multicenter, randomized, controlled study in 183 patients with documented undetectable HBV DNA while on NUCs for at least 1 year
ANRS-HB06 PEGAN Study
NUC alone (n=93)
NUC + PegIFN
Wk 0 Wk 144
HBeAg- undetectable HBV DNA
on NUCs (n=183)
Wk 96 Wk 48
NUCs Alone N=93
PegIFN + NUCs N=90 P-value
HBsAg loss (Week 48, %) 0 (0) 7 (8) 0.0057 HBsAg loss (Week 96, %) (1 endpoint) 3 (3) 7 (8) 0.1521
HBs seroconversion (Week 96, %) 1 (1) 6 (7) 0.0465
NUC alone (n=90)
Patients receiving add-on PegIFN experienced higher HBsAg loss than NUC monotherapy at W48, but without statistical difference at W96
HBsAg loss with TDF plus PEG in chronic hepatitis B (CHB): Results of a global randomized controlled trial at week 72
Start TDF during follow-up if prespecified safety criteria met
0 48 120 72
TDF + PEG
TDF+PEG TDF
24
n=186
n=184
n=185
n=185 PEG
16
TDF
Week
from Asian No cirrhosis and bridging fibrosis were excluded
HBsAg HBeAg Loss Loss 9% 29% 2.8% 25% 0% 15% 2.8% 25%
Marcellin P, et al. AASLD 2014
37
Baseline and On-Treatment Predictors of HBsAg Loss at Week 72
Univariate
P-value Multivariate
P-value Hazard ratio Multivariate
Baseline Predictors
Genotype A vs B 0.024
Study 149.-On-Treatment Predictors of HBsAg Loss at Week 72
38 Chan, EASL, 2015, O117
Sensitivity Specificity Positive
Predictive Value
Negative Predictive
Value
HBsAg decline from baseline > 1 log10 at Week 12
71% 92% 43% 97%
TDF + PegIFN 48 wk
High negative predictive values are seen among patients treated with TDF + PegIFN combination if they have:
HBsAg decline < 1 log10 IU/mL at Week 12
What can be achieved now?
High rates of virological response with low/no risk of resistance
Histological improvement
Stop progression of disease (decompensation) and reduced liver transplant
Reduced risk of HCC
?
Hepatitis B Virus therapyDisclosuresSlide Number 3Slide Number 4What can be achieved nowLong-term follow-up of immune tolerant patientsWhat can be achieved now inimmune tolerant patients?HBV DNA suppression inimmune tolerant patientsWhat can be achieved now?Slide Number 10Approved Agents used to Treat HBVSlide Number 12Therapeutic Strategies for Chronic Hepatitis BPeginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Positive PatientsPeginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Negative PatientsSlide Number 16Slide Number 17Slide Number 18Slide Number 19Therapeutic Strategies for Chronic Hepatitis BHigh virological responses withlong-term ETV or TDFCIBERHEP: Efficacy of TDF in Treatment nave and Treatment Experienced patientsVIREAL study: high rates of virological response, regardless of ageLiver fibrosis regression and cirrhosis reversal over 5 years of treatment with TDFCharacteristics of patients shown to be associated with reversal of cirrhosis with TDFRisk of HCC is predicted to be decreased with long-term therapyJapanese cohorts: significantly reduced HCC incidence with ETV compared with controlsin cirrhotic patientsLower risk of death/transplantation with ETV than with LAMWhen to stop NA therapy?Off-therapy durability of response toETV in HBeAg-negative CHB from TaiwanqHBsAg predicts HBsAg loss andHBV relapse after LAM discontinuation in HBeAg -veStopping TDF After Long-Term Virologic Suppression in HBeAg-Negative CHBSlide Number 33Slide Number 34HBsAg Clearance After Addition of PegIFN for 48 Weeks in HBeAg-Negative CHB Patients on NUCsHBsAg loss with TDF plus PEG in chronic hepatitis B (CHB): Results of a global randomized controlled trial at week 72Slide Number 37Slide Number 38What can be achieved now?