what is the hbv cure rate with current...
TRANSCRIPT
What is the HBV cure rate
with current therapy
Harry L.A. Janssen
Francis Family Chair of Liver Research
Director Division of Hepatology
Director Toronto Centre for Liver Disease
Toronto General Hospital
University of Toronto, Canada
Nov 2018
Toronto
Treatment of Hepatitis B
2018Easy
40 years
1991
Challenge1978
No Treatment
Antiviral therapy for Hepatitis B
Primary aims achieved
• Past three decades– Conventional interferon– PEG interferon– Nucleotide analogues (seven)
• Lamivudine, adefovir, entecavir, telbivudine, tenofovir, emtricitabine, TAF
• Have been shown to delay progression of cirrhosis• Reduce (but not eliminate) the risk of HCC• Improve survival• Reduce the need for liver transplantation• A cure is seldom achieved; cessation of treatment is possible in
some
Current treatment options for hepatitis B
Peg-interferon NAs
Pros
Cons
• Finite duration
• Higher sustained off-treatment
response
• No resistance
• Potent viral inhibition
• Well tolerated
• Oral administration
• Side effects
• Injection
• Contraindications
• Sustained off-treatment
responses in minority
• Long/indefinite treatment
• Long-term toxicity unknown
• Potential for resistance
What does cure of HBV mean?
Several definitions are used
cccDNA: covalently closed circular DNA; HBeAg: hepatitis B ‘e’ antigen;
HBsAg: hepatitis B surface antigen; IFN: interferon; NA: nucleos(t)ide analogue
Durantel D, et al. J Hepatol 2016;64:S117–31
Achieved
with NAs
Achieved with IFN-based
therapy in a small
proportion of patients
Currently
unachievable
Decreased viral RNA and
protein synthesis,
HBsAg loss and
seroconversion
Elimination of cccDNA
but persistence of
integrated viral DNA
Functional cure Complete cure
Nucleos(t)ide analogue-
induced virus suppression
(HBe seroconversion=20%)
No treatment
Virus suppression
HBsAg decline in patients treated with ETV or TDF
need for host immune response
HBeAg+
HBeAg-
∕∕
Low ALT
p =0.006
High ALT
p =0.02
∕∕
Zoutendijk et al. J Inf Dis 2011
•Patients treated with ETV or TDF who achieved a Virologic Response (VR)
•No difference in HBsAg decline between treatment regimens
HBeAg-positive HBeAg-negative HBeAg-positive
High ALT
Years to 1log decline* 6.6 [1.7; 17.5] 8.0 [0.5; 14.9] 3.6 [1.3; 16.7]
Years to HBsAg loss* 36.4 [9.6; 98.3] 38.9 [1.3; 80.5] 19.5 [7.3; 99.9]
0
34
50
55
21
26
40 40
3
811 12
1
68
10
0
10
20
30
40
50
60
1 3 5 7
Resp
on
se (
%)
Follow-up (years)
HBeAg loss
HBeAg seroconversion
HBsAg loss
HBsAg seroconversion
Serological response to TDF therapy in HBeAg
positive patients: 8 year follow-up
Marcellin et al, NEJM 2008; Heathcote et al, Gastro 2011 Snow-Lampart et al, Hepatology
2011; Marcellin et al, Lancet 2013; Buti et al, Dig Dis Sci 2015
Per protocol
analysis
TDF Treatment at Year 8: Primary and
Secondary Endpoints
1Missing/addition of FTC = failure [LTE-TDF]); 2Missing=excluded/addition of FTC = included.; 3Kaplan-Meier
(KM-ITT); NA = not applicable
%
HBeAg-
n=375
HBeAg+
n=266
HBV DNA ITT1 Observed2 ITT Observed
<69 IU/mL 75 99.6 58 98
<29 IU/mL 74 99 58 97
HBeAg
Loss / seroconversion NA NA 32 / 21 47 / 31
HBsAg loss / seroconversion 1.1 / 0.7 1.1 / 0.7 12.9 / 10.3 11.5 / 8.5
Marcellin et al. J Hep 2014
• 110/5409 patients had NA-induced HBsAg loss (0.33 annual clearance rate) and
discontinued NA (LAM,ETV)
• Of these 110 patients, 1 developed HCC and 1 died
NA-induced HBsAg seroclearance in
Relation to Outcome
Kim et al, Gut 2013
Response to PEG-IFN 6 months
post treatment
Pa
tie
nts
(%
)
32
14
41
3
29
7
32
7
0
19
59
4
0
10
20
30
40
50
60
70
HBeAgseroconversion
HBV DNA <400copies/ml
Normal ALT HBsAg loss
HBeAg(+) PEG-IFNalfa-2a
Lau, NEJM 2005; Janssen, Lancet 2005; Marcellin, NEJM 2004.
Treatment duration 48 weeks
HBeAg (+) PEG-IFN
alfa-2b
HBeAg (-) PEG-IFN
alfa-2a
HBeAg
negative
ALT
normal
HBV DNA
<10,000
copies/ml
HBsAg
negative
0
10
20
30
40
50
60
70
80
90
100
Pe
rce
nta
ge
of
init
ial re
sp
on
de
rs (
%)
81%78%
58%
30%
45%
HBV DNA
<400
copies/ml
3-year follow up of HBeAg responders
to PEG-IFNα-2b: HBeAg-positive CHB
n=64 n=172
11%
HBsAg
negative
overall
Buster et al. Gastroenterology 2008
HBeAg loss* and HBsAg loss
cross-sectional data
H Choi et al. AASLD 2018
HBsAg Loss after 13 Years of Follow-Up of Interferon-
Alpha Treatment for HBeAg-positive CHB: ELITE-B Study
HBsAg loss
Kaplan Meier Curve
* Partly have HBeAg negative active CHB
Mainly Caucasian patients
Start TDF during follow-upif prespecified safety criteria met
• Randomized, controlled, open-label study (N=740)
– Stratified by screening HBeAg status and HBV genotype
• Inclusion criteria
– HBeAg+ and HBV DNA ≥20,000 IU/mL; HBeAg- and HBV DNA ≥2,000 IU/mL
– ALT >54 and ≤400 U/L (men); ALT >36 and ≤300 U/L (women)
– No bridging fibrosis or cirrhosis on liver biopsy or by transient elastography
0 48 12072
TDF + PEG
TDF+PEG → TDF
24
n=186
n=184
n=185
n=185 PEG
16
TDF
Week
TDF vs PEG IFN vs Combination
TDF vs PEG IFN vs Combination
Change in Serum HBsAg Levels
-1,4
-1,2
-1
-0,8
-0,6
-0,4
-0,2
0
0 10 20 30 40 50
Study Week
Mea
n C
han
ge
Fro
m B
aselin
e(log
10
IU/m
L)
3 patients who were re-treated at Week 48 were excluded from Week 48 calculations.
Error bars represent 95% confidence intervals.
TDF+PEG 16 wk
→TDF 32 wk
TDF + PEG 48 wk
-0.3 log
PEG 48 wk
TDF 120 wk
-0.5 log
-0.8 log
-1.1 log
p<.001
p=.016
p<.001
Marcellin et al. Lancet 2015
Patients
w
ith
HB
sA
g L
oss,
Kapla
n-M
eie
r E
stim
ate
(%
)
0.10
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0.00
48 weeks
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Week
0.15
0.14
0.13
0.12
0.11
72 weeks
7 patients had HBsAg seroreversion on or after Week 48 (4 [TDF + PEG 48 wk],
3 [TDF + PEG 16 wk →TDF 32 wk])
– 5/7 had ≤1 week of therapy after HBsAg loss
TDF + PEG 16 wk →TDF 32 wk
TDF + PEG 48 wk 9.0%
0%
2.8%
2.8%
p=0.003
p<0.001PEG 48 wk
TDF 120 wk
TDF vs PEG IFN vs Combination
HBsAg Loss through week 72
Marcellin et al. Lancet 2015
– HBeAg positive study
– Multicenter, open-label, randomized controlled trial
36
Entecavir 0.5 mg daily
0 4812 24
0 12 24 36 48
Pegi-IFN alfa-2a 180g
Entecavir 0.5 mg daily
Entecavir 0.5 mg daily
Entecavir 0.5 mg daily
Entecavir 0.5 mg daily
Follow-up
Entecavir 0.5 mg daily Follow-up
48 72 96
48 72 96
Response? *
Response: combined presence of HBeAg loss and HBV DNA level < 200 IU/ml at week 48
ETV and PEG-IFN (ARES Study)
Brouwer et al. Hepatology 2015
Sustained Response: ETV Peg-IFN add-on vs. ETV
ARES Study
ETV PEG-IFN add-on
ETV monotherapy
81%19% 79%21%
90%10% 25
%
75%
Continue
ETV
therapy
Continue ETV
therapy
Response
Stop Rx
Response: HBeAg loss, normal serum ALT and HBV DNA <2000 IU/mL
Sustained
Response
Sustained
Response
Brouwer et al. Hepatology 2015
Response
Stop Rx
Combination of NA and PEG-IFN ?A systematic review
▪ NA to improve IFN response in naive patients
- Sequential NA to IFN (NO)
- De-novo NA + IFN combination (few patients, GT A ?)
▪ IFN to improve NA response in naive patients
- Early add-on IFN for HBeAg pos pts (limited benefit)
- De-novo NA + IFN combination (limited benefit)
▪ IFN to improve NUC response in treated patients
- Add-on IFN to NA in HBeAg pos or HBeAg neg (limited benefit)
Viganò M, Invernizzi F, Grossi G, Lampertico P. APT 2016;
Brouwer et al. Hepatology 2015, Chi et al. CID 2017
Limted benefit: 5-10 improvement
Prediction of HBsAg loss for
NA and PEG-IFN
HBV genotype A>B>C>D
HBV DNA Low
ALT High
Viral Genome Wildtype vs PC/BCP
HBsAg Low
Conclusions
▪ Functional cure as indicated by HBsAg loss/seroconversion is very difficult to achieve in CHB with current therapy
▪ NA therapy is most probably indefinite because the majority of HBV patients relapse after stopping NA
▪ PEG-IFN whether or not in combination with NA has more potential for HBsAg seroconversion, particularly long-term
▪ HBV genotype, HBVDNA , AST and HBsAg levels pre-treatment may help to predict functional cure
▪ Monitoring HBsAg may help us identify patients who will reach functional cure
▪ New treatments targets are warranted to reach cure of HBV