Hepatitis B 2014
Therapy beyond the guidelines
IsASL 2014
Geoffrey Dusheiko
University College London Medical School
Royal Free Hospital
London
Therapeutic goals in hepatitis B1–3
Prevention
of HCC
HBeAg
clearance
Prevention of
disease-related
mortality
Prevention of
decompensated cirrhosis
Reversal of
fibrosis/cirrhosis
Control of
viral replication
Primary aim
1. EASL Clinical Practice Guidelines. J Hepatol 2012;57:167–85;
2. Liaw YF, et al. Hepatol Int 2012;6:809–10;
3. Lok A, McMahon B. Hepatology 2009;50:661–2,1–36.
HBsAg: hepatitis B surface antigen
Treatment forms part of the control of the
disease, in addition to vaccination
• Vaccination coverage is not universal1,2
• The burden of the consequences of HBV continues to
grow
• Very large residuum of chronic hepatitis3
• Patients are only diagnosed when disease has
progressed – silent disease3
• Control of viral replication achieved
– In a minority with interferon
– With nucleoside analogues given for prolonged period in
majority
1. WHO Global policy report on prevention and control of viral hepatitis 2013;
2. van Damme P, et al. BMJ 2013;346:f4057 doi: 10.1136/bmj.f4057;
3. Blachier M, et al. J Hepatol 2013;58:593–608.
Liver fibrosis regression and cirrhosis reversal
over 5 years of TDF treatment
– N=348 had biopsies at baseline and
Year 5
– N=96 with cirrhosis
• 74% (71/96) had reversal
of cirrhosis
Ishak FibrosisScore
P<0.001
P<0.001
100
80
Patients (%)
• TDF vs ADV for 48 weeks then
open-label TDF in HBeAgand HBeAg+ patients
(Studies 102 and 103)
Missing
6
5
4
3
2
1
0
60
40
20
0
Baseline
Marcellin P, et al. Lancet 2013;381:468–75.
Year 1
Year 5
Histologically evaluable patients in the long-term histology cohort
344 patients had biopsies at baseline, Year 1 and Year 5.
0.4
P=0.001
0.3
0.2
0.1
0.0
0
No at risk
ETV
482
Control 69
Cumulative probability
Cumulative probability
All hepatic events
0.5
12
24
36
48
Follow-up duration (months)
442
342
179
74
62
51
44
37
20
36
0.2
P<0.001
0.1
0.0
0
No at risk
ETV
482
Control
69
12
24
36
48
Follow-up duration (months)
473
383
214
93
66
63
61
52
Wong GL, et al. Hepatology 2013;58:1537–47.
0.4
0.3
0.1
0.0
No at risk
ETV
Control
482
69
12
24
36
48
Follow-up duration (months)
466
365
194
81
65
60
52
45
60
20
41
All-cause mortality
0.3
0.2
P<0.001
0.1
0.0
60
23
48
P=0.036
0.2
0
ETV
Control
Liver-related mortality
0.3
HCC
0.5
60
Cumulative probability
Cumulative probability
Cumulative probability of outcome:
ETV vs historical control in cirrhotic patients
0
No at risk
ETV
Control
482
69
12
24
36
48
Follow-up duration (months)
473
383
214
93
66
63
61
52
60
23
48
Barriers to cure
• cccDNA eradication, silencing or degradation
• Overcoming dysfunctional or insufficient T cell,
natural killer cell and B cell response
Frequency of HBV genotypes in
HBeAg +ve and HBeAg -ve patients
HBeAg+ve Patients
HBeAg-ve Patients
(n=510)
(n=184)
80
80
% Patients
100
% Patients
100
60
36%
40
29%
62%
60
40
20%
11%
20
17%
20
<1%
1%
2%
13%
6%
2%
<1%
0%
0
0
A
B
C
D
E
HBV genotype
Westland C, et al. Gastroenterology 2003; 125:107-16.
F
G
A
B
C
D
E
HBV genotype
F
G
Age in years at HBeAg clearance
Genotype n
Age at HBeAg clearance
(50th percentile)
Age in years at
HBeAg clearance
(75th percentile)
A2
34
19.4
32
B6
6
19.5
27
C2
363
47.8
58
D
305
18
27
F1
126
16
24
McMahon et al Hep Int 2009 3:334-342
Percentage of patients (%)
Percentage of patients (%)
Response to PEG-IFN in HBeAg positive
according to HBV genotype
n=90
n=23
n=39
n=103
n=90
n=23
1. Janssen HL, et al. Lancet 2005; 363:123-129. 2. Flink HJ, et al. Am J Gastroenterol 2006; 101:297-303.
n=39
n=103
Predicting response: Neptune study: Factors associated with response
BASELINE ALT strata and on treatment HBsAg predicts response
Liaw et al HEPATOLOGY 2011;54:1591-1599
Prediction of sustained response to peginterferon alfa‐2b for hepatitis B e
antigen–positive chronic hepatitis B using on‐treatment hepatitis B surface
antigen decline
Sonneveld Hepatology: 52: 1251-1257, 29 JUL 2010
HBsAg decline according to HBV genotype
IFN treatment. HBeAg positive
Sonneveld M et J Virol 17 (1) 9-17 2012; Buster CJ, et al. Gastroenterology 2008;135 459–67 2. Marcellin P, et al. Gastroenterology
2009;136:2169–2179; 3. Flink HJ et al. Am J Gastroenterol 2006;101:297–303.;Sonneveld M et al Antiviral Therapy 17: 9-17 2012
PEG IFN: Stopping rules at week 12 and 24 for
response?
Week
Week 12
Week 24
HBV Genotype
Applied Rule
N Identified
NPV Response
A (n = 55)
No decline
13 (24%)
100%
B (n = 120)
>20,000 IU/mL
24 (20%)
92%
C (n = 225)
>20,000 IU/mL
45 (20%)
98%
D (n = 54)
No decline
33 (61%)
97%
A (n = 55)
>20,000 IU/mL
24 (44%)
96%
B (n = 122)
>20,000 IU/mL
16 (13%)
100%
C (n = 224)
>20,000 IU/mL
27 (12%)
100%
D (n = 53)
>20,000 IU/mL
36 (68%)
100%
Response outcome: HBeAg Loss with HBV DNA <2,000 IU/mL
Across HBV genotypes in patients treated with peginterferon monotherapy for 1 year
Sonneveld et al Hepatology epub 29 JUL 2013
Quantitative Virologic and Serologic Responses
0
0
HBV DNAa 24
24
48
48
Lambda
Posttreatment
-0.5
**
-1.5
Change from baseline, Mean log10 ± SE
72
72 Week
-2.5
-3.5
0.0
0
0
qHBsAgb
*
24
24
48
48
72
72 Week
Posttreatment
0.0
-0.5
0
0
qHBeAgc
24
24
48
48
■ First 24 weeks: greater early
declines in HBV DNA and qHBsAg
with Lambda
■ End of treatment: responses
comparable for Lambda vs alfa
*
-0.5
-1.0
72
72 Week
■ Posttreatment: HBV DNA and
qHBeAg responses favor alfa
Posttreatment
*
* Significant difference (P < 0.05)
-1.0
-1.5
-2.0
alfa
a Roche
COBAS® TaqMan HPS assay LLOQ 29 IU/mL, LLOD 10 IU/mL
b Abbott Architect assay, linear range, 0.05–250 IU/mL
c Abbott Architect assay, linear range 0.22–56.70 PEIU/mL
Chan HL, et al. EASL 2014.
HBeAg Seroconversion
LAMBDA INTEFERON
Through Week 24 Post-Dosing
Week 48
Lambda 180 µg
(N = 80)
Alfa 180 µg
(N = 83)
14/80 (18%)
14/83 (17%)
Seroreversion: – 4 patients
Other: – 3 patients
Seroreversion: – 3 patients
Other: – 1 patient
New seroconversion:
+ 4 patients
New seroconversion:
+ 15 patients
11/80 (14%)
25/83 (30%)
Week 24
post-dosing
EASL 2014 Kindly supplied by Chan et al
Effective viral suppression nucleoside
analogues
• Oral antivirals for CHB need to be given
long term in the vast majority of patients
• Long term management requires effective viral
suppression without promoting selection of
treatment-resistant HBV mutations
• Avoiding long term toxicities
EASL Clinical Practice Guidelines. J Hepatol 2012;57:167–85.
CHB: chronic hepatitis B
High viral load patients can achieve
HBV DNA negativity with long-term TDF
129 patients with HBV DNA >9 log10 IU/mL
(20% of overall population)
HBV DNA <400 copies/mL (%)
100
80
Patients with HBV DNA <400 copies/mL at Week 240:
Non-HVL: 99.2%
HVL: 98.3%
60
40
20
non-HVL
HVL
0
0 8 16 24 32 40 48 56 64 72 80 88 96 108 120 132 144 156 168 180 192 204 216 228 240
Weeks on study
Gordon SC, et al. Hepatology 2013;58:505–13.
HVL: high viral load
Entecavir treatment for chronic hepatitis B: Adaptation is not needed for
the majority of naïve patients with a partial virological response
Zoutendijk Hepatology Volume 54, Issue s 443–451, August 2011
TDF-ETV combination therapy in multi-drug
resistant patients: European evidence
• Multicentre, EU open-label cohort of
57 patients previously treated with a median
of 3 lines of antiviral therapy
• Baseline HBV DNA: 1.5 x 104 IU/mL
• Median treatment duration with TDF + ETV:
21 months
HBV DNA (IU/mL)
1010
108
106
104
LLD
102
BL
3
6
9
12
15
18
21
24
27
34
28
24
17
Time (months)
N=
57
57
Petersen J, et al. J Hepatol 2012;56:520–6.
51
48
42
40
Telbivudine renal function
Gane et al Gastroenterology Jan 2014
Effect of HBV Genotype on HBsAg kinetics:
telbivudine
* p<0.0001
** p=0.0013
Wursthorn K, et al. Hepatology 2010; 52: 1611-1620.
PEG-IFN add-on results in more viral decline
HBsAg
qHBsAg decline (log IU/ml)
Randomise
d
0.0
Follow-up
-0.5
p=0.009
-1.0
-1.5
36
48
60
72
84
Randomise
d
-0.0
-0.0
-0.2
-0.2
-0.4
96
24
36
48
60
72
84
96
Treatment week
HBV DNA
Randomise
d
0.0
Follow-up
ETV
ETV PEG-IFN add-on
-0.5
-1.0
p=0.087
-1.5
-2.0
24
-0.4
Follow-up
p=0.001
Treatment week
HBV DNA decline (log IU/ml)
24
HBsAg decline (log IU/ml)
qHBeAg decline (log Iu/ml)
HBeAg
36
48
60
72
Treatment week
84
96
Brouwer, W.P. et al, EASL 2014 abstract #O3
Week 96: PEG-IFN add-on results in more
response
% of patients with response
40
40
ETV
31
3030
%Responseat week96
ETV PEG-IFN add-on
p=0.107
34
31
20
26
26
24
24
22
20
p=0.059
p=0.029
20
20
13
11
10
14
11
10
0
0
18/90
26/85
HBeAg loss
& HBV DNA <200 IU/mL
10/90
20/85
HBeAg seroconversion
& HBV DNA <200 IU/mL
Note: patients with a response at week 48 stopped all treatment at week 72.
This is a cross-sectional analysis at week 96
13/90
22/85
HBsAg <1000 IU/mL
Brouwer, W.P. et al, EASL 2014 abstract
#O3
Entecavir monotherapy is effective in
suppressing hepatitis B virus after liver
transplantation
80 consecutive patients
NO HBIG
Fung J, et al. Gastroenterology 2011; 141:1212-19.
Infant HBsAg seropositivity
Lamivudine
Study or Subgroup
Events Total
No intervention
Events
Odds Ratio
Total Weight
Odds Ratio
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
1.6.1 No intervention
Feng 2007
7
48
16
42
21.7%
0.28 [0.10, 0.77]
Guo 2008
4
70
12
40
21.4%
0.14 [0.04, 0.48]
Han 2005
0
43
5
35
8.9%
0.06 [0.00, 1.20]
Li 2006a
1
36
7
44
9.1%
0.15 [0.02, 1.29]
Zhang 2010a
1
50
8
50
11.6%
0.11 [0.01, 0.89]
211
72.7%
0.17 [0.09, 0.33]
59
27.3%
0.34 [0.14, 0.80]
59
27.3%
0.34 [0.14, 0.80]
270 100.0%
0.22 [0.13, 0.36]
Subtotal (95% CI)
Total events
247
13
48
Heterogeneity: Chi² = 1.62, df = 4 (P = 0.81); I² = 0%
Test for overall effect: Z = 5.25 (P < 0.00001)
1.6.2 Placebo
Xu 2009
10
Subtotal (95% CI)
Total events
56
23
56
10
23
Heterogeneity: Not applicable
Test for overall effect: Z = 2.45 (P = 0.01)
Total (95% CI)
Total events
303
23
71
Heterogeneity: Chi² = 2.97, df = 5 (P = 0.70); I² = 0%
Test for overall effect: Z = 5.77 (P < 0.00001)
0.005
0.1
1
10
200
Favours lamivudine Favours no intervention
Test for subgroup differences: Chi² = 1.61, df = 1 (P = 0.20), I² = 37.9%
BMJ Technology Assessment Group, London
Tenofovir improves the outcome in patients with spontaneous
reactivation of hepatitis B presenting as acute‐on‐chronic liver
failure
Garg et al Hepatology 53: 774-780, 3 FEB 2011
Future directions: new targets
RNA interference,
e.g. ARC-520
Immune modulation
• Toll-like receptors
agonists, e.g.
GS-9620
• Anti-PD-1 mAb,
e.g. BMS-936559
• CYT107
• GI13000
Inhibitors of HBsAg
release, e.g. REP 9AC
Surface
proteins
HBx
Polymerase
pgRNA
Core
cccDNA
Polymerase
inhibitors
• Nucleoside
analogues, e.g.
emtricitabine,
amdoxovir,
MIV-210
• Non-nucleoside,
e.g. LB80380
rcDNA
Endosome
Entry inhibitors
• Lipopeptides, e.g.
Myrcludex-B
Targeting
cccDNA
Development stage: preclinical, clinical
Zoulim F, et al. Antiviral Res 2012;96(2):256–9; HBF Drug Watch, Available at:
http://www.hepb.org/professionals/hbf_drug_watch.htm.
Inhibition of nucleocapsid
assembly, e.g. Bay 41-4109,
NVR1221
New Agents
Strategy
HBV life cycle
Immunotherapeutic
Target
Agents
HBV Pol
TAF
Viral entry
Myrcludex-B
cccDNA
Zinc finger nucleases
cccDNA conversion
inhibitors
mRNA transcription/ stability
Zinc finger proteins
Epigenetic silencers
Viral assembly
HAPs
Phenylpropenamides
HBV antigen secretion
REP 9AC’
Small molecule inhibitors of HBsAg secretion
e.g. glucovirs
e.g. triazolo-pyrimidines
Cytokines
rIL-7
rIL-21
TLR agonists
TLR7 (GS-9620)
Therapeutic vaccines
Adeno-virus
approaches (TG1050)
Tarmogen
(GI-13020)
Blocking
T cell inhibitory receptors
Anti-PD-1 moAB
(BMS936558)
Anti-PD-L1 moAb (BMS936559)
Intrahepatic blocking of
suppressive cytokines /
regulatory T cells
TGF-β
inhibitors
T reg depletion (e.g. α-CD25, daclizumab)
RNA silencing
Antisense OGNs
Ribozymes
RNAi
PegIFN-λ1a (IL29)
Courtesy S Locarnini
What Might a HBV Curative Regimen
Look Like?
Potent NA
agent to prevent viral spread and cccDNA
re-amplification

cccDNA
Inhibitor
safe and selective agent to reduce or
silence cccDNA

Immune
Activator
agent(s) to activate specific antiviral
immune responses or relieve
repression/exhaustion of the system

HBV Antigen
Inhibitor
agent(s) to block/inhibit the HBV life-cycle
[entry, cell-spread, capsid assembly, HBx,
HBeAg, HBsAg]
Courtesy S Locarnini
cccDNA levels can be depleted in vitro
with IFN
***
120
100
100
Day 0–10 LAM
80
Day 0–3
60
40
Day 0–7
20
Day 0–10
IFN
**
120
100
% of cccDNA
120
% of cccDNA
% of HBeAg
**
80
60
40
20
0
10
20
LAM
Days
Day
0–3
Infection
7
***
Infection
60
Mock
LAM
IFN-
40
20
HBeAg
i/c HBV DNA
cccDNA
***
HBV DNA
cccDNA
Lucifora J, et al. Science 2014;343:1221–8.
10 12
18 Days
HBeAg
i/c HBV DNA
cccDNA
IFN-
**
140
**
***
**
**
120
100
80
80
60
40
20
0
HBeAg
15
Analyses
0
100
80
10
ETV
**
***
5
Days
13 Days
**
120
0
% of indicated markers
***
Day
Day
0–7 0–10
IFN-
Treatment
**
***
**
100
40
Analyses
0
% of HBV replication
markers
% of indicated markers
120
Day 0–14
Day 3–14
IFN
Day 7–14
Day 10–14
60
0
Mock
30
Primary human hepatocytes
80
20
0
0
Mock
Mock
IFN-
LAM
ETV
60
40
20
Mock
IFN-
ETV ETV + IFN-
In HepaRG cells unless stated
*P<0.05; **P<0.01; ***P<0.001
Stage
Pattern
Current treatment
Curative treatment
Immune
tolerant
High level replication
Minimal disease
Stage seen in many children
Interferon generally ineffective
Maintenance therapy
nucleosides required
Benefit if HBsAg loss at early
stage
Obviates progression
Direct inhibition
Immune activation?
Immune
active
Raised ALT
Histological activity
HBeAg to anti-HBe
Fibrosis can develop
Age of seroconversion +
genotype
Suitable for treatment with
interferon or nucleoside
Risk declines
Direct inhibition
Immune activation feasible
HBeAg
negative
hepatitis B
Anti-HBe positive
Ongoing replication
Usually BCP mutation pre-core
promoter mutation
Exarcerbations
Nucleoside analogue
Less commonly IFN
Older patients
Progressive disease
Direct inhibition
Immune activation feasible
Reactivation:
Acute on
chronic
HBV DNA elevated
ALT elevated
High risk if cirrhosis
Curative treatment would
prevent
Urgent intervention required
Inactive
carrier
HBV DNA < 2000 iu/ml
ALT normal
Risk of cirrhosis declines
HCC risk lower
Functional cure
HBsAg loss obviates frequent
monitoring
Conclusions
•
Need to identify patients with
•
Likely benefit from short term nucleoside analogue, interferon, or
combined use
•
(Necessity) to initiate nucleoside analogue therapy
•
Benefit of maintained suppression on natural history disease;
•
•
Goal: To achieve effect with finite therapy
To initiate treatment early adulthood to mid life:
•
HBsAg loss or functional cure off treatment
•
Barriers to cure will need to be overcome
•
New drugs required to affect ccc DNA pathway and immune response
•
Will likely translate into same benefit avoiding prolonged exposure

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Use of Biomarkers to Monitor HBV therapy